Introducing Lyostar III

WWW.GILYOS.COM

WWW.SPScientific.COM

Introduction of the new

Freeze Dryer

Enabling Maximum Process Control in Freeze Drying

Emerging Technologies in Freeze Drying, Cambridge, UK, 11 May 2011

WWW.GILYOS.COM

WWW.SPScientific.COM 2

Cutting edge Research & Development freeze dryer for lyophilization scientists, developed by SP Scientific in conjunction with freeze – drying experts.

Process Analytical Technology (PAT) Features:

• SMARTTM Freeze Dryer Technology

• ControLyoTM Nucleation on Demand Technology

- Introduction -

WWW.GILYOS.COM


• Development Tool based on Advanced Process Analytical Technology: Manometric Temperature Measurement (MTM).• Non-invasive • Batch method• Available on FTS LyoStarTM Freeze Dryer since 2006

Now completed by an additional technology:

SMARTTM and ControLyoTM

• Allows control of nucleation of product solution at defined temperatures during the freezing phase.

• Now Available on the new FTS/SP Scientific LyoStarTM 3 development freeze dryer.

WWW.GILYOS.COM


• SMARTTM Freeze Dryer was a joint development between UConn and Purdue University through the Center for Pharmaceutical Processing Research (CPPR).

• What is the SMARTTM Freeze-Dryer ?Freeze Drying Process Development and Optimization by the Freeze Dryer during the First Laboratory Experiments.

SMARTTM is an expert system for freeze drying:- Automatic determination of target product temperature- Selection of optimum chamber pressure (based on target product temperature)- Dynamic adjustment of shelf temperature in primary drying

Based on some required product information (SMART settings)

NOTE: it is absolutely critical to precisely determine the critical formulation temperature of the product (e.g. by Freeze-Dry Microscopy ) this greatly affects the cycle design!!!


-SMARTTM – An Expert System-

WWW.GILYOS.COM


• MTM – Core Technology of SMARTTM

• The “MTM procedure”: – Isolate chamber from condenser for a short period of time (i.e. 25 sec):

• Monitor pressure rise,• collect pressure rise data (10 points/sec).

– Fit raw data to a pressure rise model function derived from heat and mass transfer theory (MTM equation) by non-linear regression analysis.

– DIRECT evaluation of: • Vapor pressure of ice at the sublimation interface (Pice),

• Dry product layer and stopper resistance (Rp+Rs).

– INDIRECT evaluation of additional critical product and process parameters:• Software uses fundamental steady state heat and mass transfer equations to calculate

(from Pice and Rp data) derivative parameters (Tp, dm/dt, Lice, Tb …).

SMARTTM Freeze-Dryer Technology-The Technical Concept of MTM-

WWW.GILYOS.COM


• Two operation modes:

– SMART Freeze Dryer: Use of "direct" and "indirect" parameters, automatic adjustment of shelf temperature

or chamber pressure.

– Auto-MTM: User pre-defined recipe, no automatic adjustment, requires less input parameters to SMART software.

SMARTTM Freeze-Dryer Technology-The Operation Modes-

WWW.GILYOS.COM


0 5 10 15 20 25 30 35-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Shelf Temperature Thermocouple (edge vial) Thermocouple (edge vial) Thermocouple (center vial) MTM calc. procduct temperature (interface) MTM calc. product temperature (vial bottom)

Te

mp

era

ture

(°C

)

Cycle Time (hrs)

5% (w/w) sucrose240 5mL vials, 2mL fill, A

P: 2.91cm²

Toc

: -32°C, target temperature: -35°C

predefined SMARTTM settings

automatically calculated by SMART TM (including a safety

margin)

SMART Ts auto-adjustments to keep Tp inside the defined

boundaries

Excellent agreement between Tb-TC and Tb-MTM for “typical” formulations [1].

[1] Gieseler et al. 2007, J. Pharm. Sci. 96(12):3402-3418. Full investigation of critical equipment and experimental factors for SMART technology.

SMARTTM Freeze-Dryer Technology-Smart Cycle Design-

WWW.GILYOS.COM


• SMARTTM Return on Investment • Delivers freeze-drying expertise to scientists new to freeze drying.

• Ensures freeze drying cycle development is based on sound scientific principles rather than trial and error approach.

• Reduces / eliminates dependency on thermocouple product temperature measurement:

• Batch method,• non-invasive determination of product

temperature and product resistance.

• Provides consistent, automated MTM process data which saves even experts in the field of freeze drying significant time and money.

SMARTTM Freeze-Dryer Technology-Return on Investment-

WWW.GILYOS.COM


Nucleation on Demand Technology

• Novel, patent pending approach

• Uniformly and instantaneously induce nucleation at predefined temperatures.

• Scalable from lab to production

• Requires no formulation change or introduction of foreign materials into the vial.

ControLyoTM

-Nucleation on Demand-

Why Nucleation Control?

WWW.GILYOS.COM


• Basic Principles of Nucleation

Degree of supercooling

Tn = Temperatur of Onset of Nucleation

Tf = Thermodynamic Freezing Point

• Nucleation temperature is the temperature at which ice crystal formation begins.

• Nucleation rarely occurs at the thermodynamic freezing point of the solution.

(Significant differences between lab and production environment!)

• The degree of super-cooling has a great impact on drying behavior!

ControLyoTM

-Basics of Nucleation-

M. Shon, L. Mather, 2010. The Importance of Controlling Nucleation Temperature During the Freeze Step. Intorduction of ControLyoTM Nucleation on Demand Technology on the New FTS/SP Scientific TM LyoStarTM 3 Freeze Dryer, SP Scientific, 3538 Main Street, Stone Ridge, NY.

WWW.GILYOS.COM


TEMPERATURE SAMPLE

FREEZING

POINT

SAMPLEFREEZING

POINT

TEMPERATURE

• Low degree of supercooling: Larger ice crystals larger pores in the dried matrix decrease of Rp

• High degree of supercooling: Smaller ice crystals smaller pores in the dried matrix increase of Rp

[1] Searls JA, Carpenter T, Randolph, TW., 2001. The Ice Nucleation Temperature Determines the Primary Drying Rate of Lyophilization for Samples Frozen on a Temperature Controlled Shelf. JpharmSci 90: 860-871.

For every 1 degree increase in nucleation temperature, drying times are reduced by 3%. [1]

ControLyoTM

-Basics of Nucleation-

WWW.GILYOS.COM


• Common uncontrolled nucleation during freeze dryingrandom nucleation occurred within a temperature range of 10°C and a timeframe of 48 min in this case.

Adverse effects of uncontrolled nucleation:

– Problems in scale up and process transfer

– colder nucleation higher Rp longer process time higher costs

– longer cycle less throughput more facility capacity required

– vial to vial uniformity impossible (cycle time )

Example: 5% Sucrose, 3 mL in 10 mL vials, 1 tray LyoStar 3, 3 shelf unit

ControLyoTM

-Uncontrolled Nucleation-

M. Gieseler, L. Mather, 2011. Unpublished Data, SP Scientific.

WWW.GILYOS.COM


• How does ControLyoTM work?A typical sequence for controlled nucleation:

– Equilibration of the samples at the nucleation temperature.

– Pressurization of the system with an inert gas (N2, Ar) to approximately 25 - 28 psi (1.7 - 1.9 bar).

– Equilibration of the samples. – Rapid depressurization (from 28 psi

to 1 - 2 psi/0.07 - 0.14 bar). Nucleation– Hold at nucleation temperature to

allow ice crystal growth (Ostwald ripening).

Reduce shelf temperature to complete the freezing step.

Video

ControLyoTM

-The Nucleation Procedure-

WWW.GILYOS.COM


• Controlled nucleation

DEPRESSURIZATION

NUCLEATION

Example: 5% Sucrose, 3 mL in 10 mL vials, 1 tray LyoStar 3, 3 shelf unit

ControLyoTM

-Controlled Nucleation-


WWW.GILYOS.COM


• Praxair’s ControLyoTM Technology

Implementation:Praxair: 0.6, 1 and 5 m2 freeze-dryersLyophilization Services of New England: 1 and 5 m2 freeze-dryers

• Retrofitable for SIP-rated freeze-dryers• Nucleation control at temperatures up to -1 °C • Batch sizes up to 3.150 vials (5 m2 full load)• No limitations in choice of container systems • No contaminants or changes to drug formulation

ControLyoTM

-Adaptation to your System-

WWW.GILYOS.COM


New functions implemented in LyoStarTM 3

• ControLyoTM (optional)• Allen Bradley PLC• 2 Capacitance Manometer (1 in chamber, 1 in condenser)• TDLAS readiness• Pirani / CM Differential Control software• Barometric Endpoint Control software• Vacuum ramping during primary drying• Vacuum pre-seal feature• Product driven mode• Ability to control with Pirani• Heat transfer fluid: Silicone oil

SMARTTM Freeze-Dryer Technology available as option!


-LyoStarTM 3 Innovations-

WWW.GILYOS.COM


• Benefits of ControLyoTM Technology• Acceleration of

1°drying

To achieve comparable results PRCM Diff mode was used ( Setpoint: 5 mTorr) for all runs performed.

24% (avg.) reduction in 1°drying time was achieved for Controlled Nucleation.

Example: 5% Sucrose, 3 mL in 10 mL vials, 1 tray LyoStar 3, 3 shelf unit, processed with and without controlled nucleation.

ControLyoTM

-Experimental Results-


WWW.GILYOS.COM


• Benefits of ControLyoTM Technology• Reduction in protein

aggregation • Human growth hormone (hGH)

known to be sensitive to aggregation at gas-liquid interfaces.

• Good model to test whether ControLyo™ technology creates bubbles during depressurization. Controlled Nucleation Uncontrolled Nucleation

Experiments: 2 mg/mL hGH+ 2 mM sodium phosphate + 6 mg/mL sucrose1 mL fill in 5 mL vialAssay hGH aggregation via HPLC (pre-& post-freeze drying and after 14 days at 50°C)

Michael J. Pikal, School of Pharmacy, University of Connecticut, “Understanding The Importance of Ice Nucleation Temperature in Freeze Drying”, Lyophilization of Biologicals Conference, 24th January 2011, Brussels

ControLyoTM

-Experimental Results-

WWW.GILYOS.COM


• ConclusionOver the last few years since SMART Freeze Dryer technology became available on the market, the concept of MTM and the SMART Freeze Dryer evolved as an important and valuable PAT tool for freeze-drying.

ControLyoTM allows access to a so far nearly uncontrollable part of the Freeze-Drying Process. Controlled Nucleation clearly proved to optimize batch uniformity and reduce primary drying time due to higher nucleation temperatures.

Combining both technologies in one development freeze dryer enables maximum process control for freeze drying!


-Conclusion-

WWW.GILYOS.COM


THANK YOU FOR YOUR

ATTENTION

Would you like to learn more about freeze drying ? Go to the following site to discover more about our free LyoLearn webinar series:

http://www.spscientific.com/Tech-Centers/LyoTech-Center/LyoLearn-Webinars.aspx


-Introduction of Lyostar 3-

http://www.spscientific.com/Tech-Centers/LyoTech-Center/LyoLearn-Webinars.aspx

WWW.GILYOS.COM

WWW.SPScientific.COM

21

Presented during “Emerging Technologies in Freeze Drying”, Cambridge, 11th May 2011. Event organised by BPS and BTL,

www.biopharma.co.uk

http://www.biopharma.co.uk/

Introducing Lyostar III

Technology

smart technology

additional technology

smart freeze dryer

smarttmfreeze dryer

demand technology novel

product resistance

drying process development

drying cycle development