1. Module 7: Scale Up

2. Module 7 Purpose and Objectives
Scale Up includes technical transfer. Putting a product into a different lyophilizer has considerations.
Module Objectives:
After this module, you will be able to
Know the questions to answer during the tech transfer of a product to a different lyophilizer.

3. Tech Transfer Overview
I Describe the Process
II. Essential Qualification Data for Lyo Comparisons
III. When to change your Lyo vs. When to change my process.
IV. Performance Qualification – What does the Science say is needed?
Four major steps of the Transfer Operation. Number I is a paper exercise and there is much to do. Number two is a matter of “beginning with the end in mind”. That is, when the run is complete, what data is needed to satisfy all parties. Number three is a practical discussion about technical transfer in changing to a different machine. We will discuss what can and can’t change and try to do a reality check. Number four is acknowledgement that a new performance qualification (validation) is needed and a discussion about what to do and why to do it.
Finally, we will split into two groups, regulatory and manufacturing, and jointly develop an lyo tech transfer plan.

4. I. Describe the Process Cycle
Each of the items listed here impact a lyophilized product tech transfer.
Product Physical Chemistry
Lyo Process Steps
Mechanics
Control
Reporting
Clean Up
We are going to describe these 5 attributes of the process cycle.
Product Chemistry: Mostly and hopefully, we are talking about physical chemistry only. That is, crystal formation and melt temperatures and collapse temperatures. We may also care about pH during the freezing step, but since this is the transfer of a process that has previously been developed, it is assumed that the actual chemistry has already been taken care of.
Lyo Process Steps refers to the big 4. Freezing, Sublimation, Desorption, and Stoppering.
Mechanics become quite an issue during transfer. Since lyophilization is the physical movement of a large amount of water from point A to point B, the motors and dimensions of boxes mater.
Control; Frequently when we move from one lyo to another, the control features change. We need to talk about what you have and what you need.
Reporting: Data collection may change. Is the new one at least as good as the old one?
Clean Up: Sound trivial. It could be trivial – but it probably isn’t. In any event, it will be different and needs to be addressed in a transfer document.

5. Physical Chemistry: What Matters?
Collapse Temperature
Crystalline materials – e.g. Mannitol
Re-adsorption of water - Stoppers
Component Changes
Glass interactions
Stopper formula issues
These are the elements of physical chemistry that need attention for the transfer.
Collapse Temperature: I will explain this in a minute. As a first approximation and guess, it is the most important single piece of information that is needed. It is often missing.
Crystallization: May be important – or not. If there is a lot of mannitol in the vial and we freeze incorrectly, the vials all break.
Re-absorption of water. Is the product the same amount of dry coming out of the new lyo and 6 months later from the new lyo?
Component changes: Usually, a simple tech transfer would not change either the glass or the stopper, but if it does, then it should be addressed as a major supplement. Since many QA people think that changing to a new lyo is in fact a major supplement anyway, some executives see this as a perfect time to also change the glass or rubber.
Physical Chemistry

6. Collapse
Collapse refers to melting of mostly non-ice portions of a frozen matrix.
Freezing is a ‘water purification step’. Water molecules line up with one another and exclude non-water molecules.
First we need to understand what collapse is and then we can talk about how to measure it.
When ice freezes, the water molecules align as shown in the diagram. That necessarily means that there are less of them available for solvating the drug molecules. These water crystals freeze at zero degrees C, the freezing temperature of water. And mostly it is these crystals that we sublime away during the primary drying step of lyophilization.
Meanwhile, the remainder – drug molecules, salts, excipients, and some of the water in in a non-crystalline phase called the “interstitial phase” and depending on the temperature it is either a liquid or a solid, but not probably crystalline. We need to maintain the interstitial phase as a solid (called a glass) because when it melts, and simultaneously the H20 is sublimed, the liquid settles and we get “collapse”.
Physical Chemistry

7. Recognize Collapse
Correct
Shrinkage
Meltback
Physical Chemistry

8. How to Measure Collapse Temperature
Freeze Stage Microscopy
Glass Transition Temp. Tg
Tg is a function of moisture content at the time of measurement. In that context, it is referred to as Tg’.
In freeze stage microscopy, the sample is put onto the stage of a microscope in a special holder that can submit the sample to cold temperatures and to a vacuum. The temperature is then gradually raised and the sample begins to lyophilize from the edges to the center. As the temperature goes through the collapse region, one can visually observe the interstitial melt and thus identify a collapse temperature. This method is preferable because it returns a single answer, even if the number is a range of 2 to 3 degrees.
A Glass transition is the softening of a solidified but non-crystalline material as a result of heating. Think of a had piece of plastic. Heat it up, and it will get to some temperature range where is softens. Similarly, the glass interstitial phase softens as its temperature is raised and it is most easy to analytically detect using a DSC (differential scanning calorimeter). There is however a problem with this method, namely that the DSC does not operate in vacuum and the apparent Tg (Tg’) changes with different moisture content. Although this method is used, it should probably be compared with the microscopy and if they differ, then let the microscopy prevail.
Laboratories are available to run both methods.
Physical Chemistry

9. Freeze Drying Microscopy
Like DSC, freeze-dry cryostage can reach a wide temperature range rapidly.  Currently, as a preformulation and formulation study tool, simulating the lyophilization cycle in a freeze dry cryostage provides the best platform to study thermal parameters of the protein formulations on a miniature scale.  Freeze dry microscope can predict the influence of formulations and process factors on freezing and drying.  Only a 2-3microliter sample is required for a cryostage study, which makes this technique a valuable tool to study scarce, difficult-to-obtain drugs.  It is a good tool to study the effect of freezing, rate, drying rate, thawing rate on the lyophilization cycle.  Annealing research may be advanced by the studies from freeze-dry cryostage microscope.  Because of extensive applications of lyophilization technology, and larger demand to stabilize the extremely expensive drugs (such as proteins and gene therapy drugs), it is expected that an in-process microscopic monitor should be realized in the pharmaceutical a  industries soon.
Physical Chemistry

10. Differential Scanning Calorimetry
Picture is a Mettler DSC.
DSC is a physical thermo-analytical method to measure, characterize and analyze thermal properties of materials and determine the heat capacities, melting enthalpies and transition points accordingly.  DSC scans through a temperature range at a linear rate.  Individual heaters within the instrument provide heat to sample and reference pans separately, based on the “power compensated null balance” principle.  During a physical transition,  the absorption or evolution of the energy causes an imbalance in the amount of energy supplied to that of the sample holder.  Depending on the varying thermal behavior of the sample, the energy will be taken or diffused from the sample, and the temperature difference will be sensed as an electrical signal to the computer.  As a result, an automatic adjustment of the heaters makes the temperature of the sample holder identical to the reference holder.  The electrical power needed for the compensation is equivalent to the calorimetric effect. 
Physical Chemistry

11. Tg’ and Tc Examples Compound Collapse Temp Tg’ Fructose -48 -42
Glucose
-40
-43
Maltose
-32
-30
Sorbitol
<-45
-44
Sucrose
Bovine Serum Albumin -4 -5
Dextran -9
PVP
-17
Lactose
Physical Chemistry

12. Degree of Crystallinity
Possible to estimate by DSC
Critical to reproducing sublimation results
Virtually never done due to the difficulty of reproducing the freezing conditions.
Although the DSC can easily determine the quantity of water ice in a sample, it is not scientifically justifiable to conclude that the freezing conditions within a DSC have adequately simulated those with the lyophilizer. Consequently, no one bothers to estimate % crystallinity within their formulation.
Physical Chemistry

13. Re-adsorption of Water
Assure that stopper sterilization results in a dry stopper, or else dry it in a sterile oven.
Check 6 month stability data for moisture content.
Stopper Wt = gm
3% Moisture = .03 x = 65.4mg H2O
Product = 3mL at 5% solids
.05 x 3mL = 150 mg Product after Lyo
Point = There are ~65 mg of water in stopper after steaming and getting even 3mg into the product after 6 mo will be a failure.
Moisture Spec = <2%
.02 x 150mg = 3 mg H2O max
Physical Chemistry

14. Transition
Physical
Chemistry
Process

15. Freezing Large ice crystals will reduce sublimation time.
Crystallization of excipients such as mannitol may occur and can be controlled separately from water ice.
Supercooling is when the liquid water temperature is below the freezing temperature of the solution. Freezing is an exothermic event. The latent heat given up is measured as an increase in probe temperature.
Factors that effect supercooling include
Chilling rate
Container shape and volume
Holding time
Solution particulate content
Temperature
Lyo Process Steps: Freezing

16. Enthalpy Change on Freezing
Enthalpy (symbolized H, also called heat content) is the sum of the internal energy of matter and the product of its volume multiplied by the pressure. Enthalpy is a quantifiable state function, and the total enthalpy of a system cannot be measured directly; the enthalpy change of a system is measured instead. Enthalpy can only be applied to a body at constant pressure.
Enthalpy is most useful when pressure is held constant through exposure to the surroundings, to analyze reactions that increase the volume of the system, causing it to do mechanical work on the surroundings and lose energy.
For an exothermic reaction at constant pressure, the system's change in enthalpy is equal to the energy released in the reaction, including the energy retained in the system and that lost through expansion against the surroundings.
The measured increase in thermocouple temperature during freezing is direct visual evidence of enthalpic heat release. For lyophilization, it registers the moment of crystallization within the vial that contains the thermocouple and if there are enough thermocouples, it may show the variability for freezing within the lyo load.
H = U + PV
Lyo Process Steps: Freezing

17. Annealing
Annealing is a treatment of the frozen matrix that involves raising the temperature of the ice to just below the melting point of water. For example: -7 degrees C. The temperature is then held for some reasonable time and water molecules that are in smaller crystals will dissolve and refreeze onto larger crystals. The larger crystals lead to a larger porosity and faster sublimation.
Can both lyophilizers accommodate this step. Clearly if it was used in the original cycle, it will have to be used in the new cycle. This step can become somewhat complicated in a true scale up since the rates for freezing large amounts of liquid are seldom like freezing small amounts of liquid.
Lyo Process Steps: Freezing

18. Validate an Extended Freeze
Can you freeze for too Long?
No. If you need to extend a cycle during freezing it is scientifically OK to do so. During validation, it may be useful to show that the same result is achieved with the standard freeze time and with a freeze time that is extended for 24 hours. That should be more than enough time to accommodate emergencies.
Yes. If the product is known to be unstable in the frozen state.
Lyo Process Steps: Freezing

19. Sublimation
Stay below the collapse temperature and then time is of no consequence to science.
Lyo Process Steps: Sublimation

20. Measure the Sublimation Rate
Keep it Simple
Grams refers to total grams of product solution put into the lyo.
cm2 refers to the total surface area calculated from the vial dimensions.
Hours refer to the total time between points A and B.
Picking Point B can be a little arbitrary so try to be consistent.
Compare Rate data between the 2 Lyophilizers

21. Tray Size
Vials near the tray rings dry faster than vials not near to the ring. If the trays are larger or smaller, then one can expect the drying rate to be different.
If the new chamber is not the same size as the original one, then it is quite likely that the trays may not be the same size either.
Lyo Process Steps: Sublimation

22. Changes in RATE
Other Reasons why Sublimation Rate might Change when one changes Lyophilizers
If the spacing between the shelves is different then you can expect the rates might change.
If the serpentine fluid flow path is different inside the shelves, then heat transfer may be different.
If the thickness of the shelves is different, then there may be a thermal delay or acceleration.
Lyo Process Steps: Sublimation

23. Vacuum
If the vacuum can’t be held at exactly the same level, then major differences in rate may be observed.
Vacuum plays a major role in determining the temperature of the ice.
Temperature is determined from pressure exactly as shown in the table.
Except: Pressure at the ice surface is always higher than pressure measured in the chamber.
Lyo Process Steps: Sublimation

24. Secondary Drying / Desorption
Sublimation has ended when the phase change is complete. i.e. all of the ice crystals have sublimed.
Usually, less than 15% water by weight is still present. Often, less than 2% water by weight will be present.
The goal of secondary drying is to drive away the remaining moisture by desorption.
Lyo Process Steps: Desorption

25. Langmuir Model for Adsorption
Very simple model for adsorption. Desorption is the reverse reaction.
In the case of Water, the adsorption is physisorption to be distinguished from chemisorption because the bonding is more physical than chemical in nature.
In this simple model,
Adsorption cannot proceed beyond monolayer coverage.
All sites on the surface are equivalent.
The ability of a molecule to adsorb at a given site is independent of the occupation of neighboring sites.
G + S GS
Lyo Process Steps: Desorption

26. Moisture Saturation at Equilibrium
An adsorption isotherm is a plot of the fractional coverage of the surface, θ , against pressure. The simplest physically plausible isotherm is based on three assumptions:
Adsorption cannot proceed beyond monolayer coverage.
All sites on the surface are equivalent.
The ability of a molecule to adsorb at a given site is independent of the occupation of neighboring sites.
As temperature is decreased, the adsorbed water sticks more tenaciously.
25 Pascals is about 200 mtorr.
Lowering the pressure in secondary below 25 Pa is of limited value since you can’t get it low enough to meaningfully effect the equilibrium
Lyo Process Steps: Desorption

27. Different starting points may yield different final moisture levels.
Absorption
Different starting points may yield different final moisture levels.
Best to use a measured end point such as pressure rise.
FDA guidelines point out that specific manufacturing directions or copies of actual master formulas are to be filed in applications. In order for manufacturers to write, or develop specific manufacturing instructions, development data has to be generated. These data should be collected and placed into a development report of some type.
Lyo Process Steps: Desorption

28. Transition
Process
Mechanics

29. Mechanics (Physical Comparison)
Condenser Capacity and Load
Ice surface area to Condenser capacity ratio
Isolation Valve Size and Design
Chamber Size
Vacuum Effective Pumping Speed
Refrigeration
Mechanics

30. Can the Chamber be too Big?
Run 4 Loads in the same lyophilizer.
Load 1 = Single Vial
Load 2 = Quarter Full
Load 3 = Half Full
Load 4 = Full
These four loads will lyophilize at four different rates.
{What might this mean to validation?}
Mechanics - Condenser

31. Condenser Capacity/Tray
One way to compare two lyo’s is to determine the ratio of condenser capacity to total shelf area (should be vial surface area). If the numbers for different lyo’s are similar then one might argue that the cycle rates will be similar.
Sq. Ft
Condenser Capacity
Trays
Condenser Capacity/Tray
Lyo 1 24
40L 12
3.3
Lyo 2
250
200L
120
1.7
Clearly the smaller Lyo has twice the “power” of the larger one, and consequently, the cycle used in the smaller lyo may have to be adjusted to work the same in the larger unit.
Mechanics - Condenser

32. Isolation Valve
In a rate maximized cycle, the shelf heaters will drive the sublimation to the very edge of choked flow. On changing to a different lyophilizer, it will be necessary to re-optimize the cycle.
All of the ice in the Chamber must squeeze through this opening to get into the condenser. Therefore it is possible to make the size of the valve rate limiting. When that occurs, it is called “Choked Flow”. In that instance, the chamber will not maintain pressure and its pressure will exceed that of the condenser.
Mechanics - Valve

33. External Leaks
Lyophilizers leak in air from somewhere and the leak holes are larger than the size of bacteria.
Parenteral Society specifies a leak rate of (0.02 mBar-L / sec) for a new clean empty freeze dryer.
Real rates for older equipment are closer to 0.56 mbar-L/sec
Literature reports go as high as 1mBar-L/s
Admit that Lyophilizers Leak. Be sure that the production model leaks are inconsequential.
Mechanics – Leak Rate

34. External Leaks Leak Rate Single Source & Round. Diameter = Number of
0.2µm diameter
pores
mbar-L/s
0.208µm 1
0.02 mbar-L / s
14.7µm
5,387
0.56 mbar-L / s
77.7µm
150,823
1 mbar-L / s
104µm
269,327
Calculation available at
Mechanics – Leak Rate

35. Heat Exchange Lexsol or Silicone Oil Mechanics – Exchange Fluid
Note: The refrigeration evaporator is the lyo condenser.
Lexsol or Silicone Oil
Mechanics – Exchange Fluid

36. Transition
Mechanics
Control

37. Control Product thermocouples
Capacitance manometers – chamber & condenser
Temperature – vials, drain, shelf I/O, condenser I/O
Thermal feedback to regulate shelf heat?
Pressure feedback to reduce shelf heat in the event of too much differential between chamber and condenser.
PLC’s for operational control (UPS backup)
HMI (Computer) for data collection (UPS backup)
SCADA for independent simultaneous data collection.
Suppose you are moving an approved product to a new site. What data must be collected prior to “validation”? How does validation differ from technical transfer?
1) Map the process and try to guess what might be different.
Control

38. Transition
Control
Reporting

39. Reporting Require Human Analysis. Provide a standard to check against.
Assure that data backup occurred.
Reporting

40. Transition
Reporting
Cleanup

41. Clean Up CIP & Testing Sterilization
Visually Confirmed as Clean (no glass or rubber).
TOC Swabs
Log maintained with entries for every event.
Compressor and pump oils full and clean
Lyo Area is Tidy.
Validated & Audited
Current Instrument calibrations
Filter integrity test performed pre and post sterilization.

42. Essential Qualification Data for Lyo Comparisons
What test data are required and why?
How to use the OQ data?
Shape matters
Stopper placement is an issue
Maps – why do we care?
II. Lyo comparison

43. Data Use
Physical Data – External/Internal condenser. If external, over, under, side-by? Stoppering from above or below?
Physical Data – chamber & condenser size, shelf size, distance between shelves, tray & vial size and number, fill volume, isolation valve size.
Physical Data – vacuum scfm and blank off pressure, foreline lengths, leak rates for chamber/condenser, pump down time from atmospheric.
Physical Data – heating / cooling rates. Compressor horsepower, heat exchanger size, exchange fluid type.
Location of TC’s for shelf I/O and condenser temperature.
Location of Pressure probes.
II. Lyo comparison

44. Data Use
OQ:
Shelf flatness !! Critical to stoppering. Ideal is shelves flat to within mm. Even this spec may be 5x to small.
The majority of workshops have straight edges ranging from steel rules to precision knife edges generally up to 4 ft long. Using these, departures from flatness of a surface of the order of .025mm can be readily observed against an illuminated background. For example, the Starrett company makes these in useful lengths.
II. Lyo comparison

45. Data Use OQ: Ability of the system to do the deed.
Availability of cooling ramp and heating ramp.
Max cool down rate of the empty chamber
Max cool down rate of a simulant full chamber
Max shelf heating rate
Minimum condenser temperature
Minimum system pressure
Time to attain minimum pressure of an empty dry chamber
Set point tolerances for temperature and pressure
Minimum shelf temperature
Maximum shelf temperature
Pressure data availability for all relevant ranges.
Stopper placement of identical vials and stoppers holding simulant
Choked Flow Test
II. Lyo comparison

46. Shape Matters Tray Size Chamber Size vs. Condenser Size
Chamber Size vs. Isolation Valve Diameter
Foreline length
II. Lyo comparison

47. Stopper Placement is an Issue
Do not assume it will go smoothly.
Check it out.
II. Lyo comparison

48. Maps – who cares
Sterility of the empty chamber should be mapped for uniformity. All spots must be shown to experience sterilizing conditions.
Shelf temperatures should be known! But + 2 degrees C is acceptable. Temperature of the ice and consequently catastrophic collapse is controlled by pressure. Heat input, which is quite diffuse is controlled by shelf temperature. At worst, (and unavoidable in all cases) if the shelf temperature is less uniform, then a section of the vials will dry faster than another section. Duh!
Already, due to the presence of tray rings, chamber edges, and sight glasses, some of the vials dry much faster than others. A small temperature difference in shelf uniformity is of small consequence.
Suggestion: Set the shelf uniformity spec to 1.5 or 2 times the manufacture’s specification.
II. Lyo comparison

49. Max Sublimation Rate (‘Choked Flow’)
Load all shelves and tray positions of the lyo with tray rings containing plastic film to hold water.
Transfer a weighed amount of water to each tray ring such that each is about 1” deep.
Freeze to a steady state of -40 C.
Monitor chamber and condenser pressure
Initiate vacuum to the lowest normally achievable set point (e.g. 80 mtorr) and stabilize the pressure.
Ramp temperature at 0.33 C/min

50. Max Sublimation Rate (‘Choked Flow’)
Continue the Shelf Temp Ramp to the maximum shelf temp for the heaters.
At some shelf temperature, the chamber pressure may exceed its set point (80mtorr). At that same temp, the condenser pressure may continue to hold set point. If so, that is evidence for a sublimation limit for that lyo limited by the isolation valve diameter.
Stop the run, reweigh the ice in a tared plastic bag and calculate a crude sublimation rate in gm/cm2∙hr.

51. Max Sublimation Rate (‘Choked Flow’)
Repeat the run to the point of stabilizing pressure at 80 mtorr.
Ramp the shelf temp ASAP to 2 C below the temperature where the chamber can’t maintain set point.
Hold shelf temp long enough to sublime ~15% of the water. (Use the rate calculated above to determine how long that is)
End the run and reweigh the ice.
Calculate the “maximum supportable sublimation rate” excluding the ramp time in gm/(cm2∙hr).

52. III. When and What to Change
Sterilization
Instrumentation
Vacuum
Refrigeration
Control
III. Change

53. Sterilization
No compromises. All data for the empty chamber and media fills must be perfect.
Filter integrity testing must exist between every run.
III. Change

54. Instrumentation Chamber and condenser pressure are mandatory.
You can’t do a Choked Flow Test without them.
Product Temperature measurement – doesn’t have to be direct, e.g. MTM.
Some people just don’t get it.
Drain temperature for sterilization.
All else can be compromised. More is better.
III. Change

55. Vacuum Vacuum must be adequate to run the cycle.
Backup vacuum capacity (2 pumps whenever 1 is sufficient to maintain) may save a lot.
Pump down times and ultimate vacuum (leaks happen) may be drastically improved by shortening and increasing inner diameter of the foreline.
III. Change

56. Refrigeration
According to one lyo repair firm, 40% of lyo mechanical issues trace back to faulty refrigeration. Don’t compromise on refrigeration maintenance.
Refrigeration capacity will be sufficient, or else the machine will not run the cycle.
Look at the loaded condition maximum cooling rate OQ test.
Check especially that the compressors can maintain the coldest loaded shelf temperature with the condensers completely cold. Many older units can’t do this.
A currently popular cycle step is to initiate vacuum and then hold the frozen shelf temp. (e.g. -50C) for 30 minutes prior to initiating the 1st ramp. Since the condenser must now be turned on, compressors are challenged.
III. Change

57. Controls
Lack of a cooling ramp may be adequately overcome by stair steps.
Feedback control to the shelf heaters from either product TC’s or chamber pressure is unusual for cycles but common for lyophilizers. Regulated cycles that use feedback control are rare because the cycle length changes (for good reason) noticeably with normal variation to a single lot size.
PLC’s, HMI’s and SCADA backup are virtually required.
III. Change

58. PQ & Technology Transfer
Sterility
Final Moisture, Activity & Stability
Reconstitution
Appearance
Lot Size
Number of Runs
Simulants
IV. PQ

59. Sterility
Empty chamber 3x
Media fills in a similar vial.
IV. PQ

60. Moisture/Activity/Stability
Measure Moisture and Drug activity immediately and put on to accelerated stability – not less than 6 months. Moisture cannot be lyophilized out of a stopper. But it comes out over the 1st 6 months. And it goes into the product.
Best done with a full load of the real drug.
2nd best, done with a simulant to keep the number of vials the same as a full load.
IV. PQ

61. Reconstitution Poor reconstitution is caused by
Partial collapse / shrinkage
Low surface area due to increased crystallization during freezing or just a different ice structure. – changing the freezing conditions often causes problems.
IV. PQ

62. Appearance
Change the conditions and you change the appearance. – Be Prepared (for a shock).
It will probably be necessary to change the cycle in a new lyophilizer in order to reproduce the appearance from some other lyophilizer.
IV. PQ

63. Lot Size
Run a minimum lot size just to show you can, but validate (3x or 5x) at the full lot size.
Sublimation times are ice volume dependent. You must use a full load to assure that you can do a full load.
IV. PQ

64. Number of Runs
Stress testing or trying to validate a range for temperature and pressure is “nice” but usually not practical. Furthermore, any deviations in pressure and temperature are not likely to stay within the validated range. When operating correctly, temperature will hold to within + 2 degrees and pressure should be controlled to within + 10 mTorr. When these parameters stray, they don’t usually stay close!
Time deviations should be scientifically justified (such as nearly unlimited time at -50 C) and then validated to some reasonably long interval.
IV. PQ

65. Simulant
Product simulants can be used to bulk up a validation load and thereby conserve expensive product.
Simulants can possess most of the properties of the lyophilized cake including especially appearance. Appearance is an important simulant property because it assures that the ice structure and thus the sublimation time is somewhat similar to the product.
FDA has always required at least one full load without simulant.
IV. PQ

66. 7.1 Exercise Outline a Tech Transfer Plan Current Process Description
Equipment Comparison at contract vendors
Existing OQ Data Desired
New Validations OQ/PQ

67. Product Description
Product is a peptide – no sulfhydrals: fill vol = 1mL
Collapse Temp is ~ -15 C
Protective agent: Albumin, 2%, also adds bulk.
Surfactant: Polysorbate 80, aids dissolution
Citrate Sodium for tonicity and pH.
pH: 5.2, aqueous
Activity decreases ~0.5% every 12 hours post compounding. Decrease is assumed linear during the 1st 12 hours.

68. Original Lyo Description
Chamber size: 200 ft2
10 shelves, 5 ft wide x 4 ft deep
Used 4’x4’ of each shelf with 8 each, 1 x 2 trays.
Vial dia = 17mm, 660 vials per tray
Full load = 660mL x 80 trays = 52,800 1cc units
Intershelf spacing = 4”
External condenser capacity: 250 liters
Isolation Valve = 7” ID with butterfly motion internal.
Two Vacuum pumps in parallel each rated for 200 scfm with about 20 ft of 4” pipe leading to chamber and condenser inlets.

69. Planned Lyo after Transfer
Chamber size: 360 ft2
12 shelves, 5 ft wide x 6 ft deep
Use all of each shelf with 15 each, 1’ x 2’ trays.
Vial dia = 17mm, 660 vials per tray
Full load = 660mL x 180 trays = 118,800 1cc units
Intershelf spacing = 2.5” (vial height 1.49”)
External condenser capacity: 600 liters
Isolation Valve = 12” ID with butterfly motion internal.
Two Vacuum pumps in parallel each rated for 300 scfm with about 20 ft of 4” pipe leading to chamber and condenser inlets.

70. Original Cycle