Application of PAT in FreezeDrying of Biopharmaceuticals

Rakhi B. Shah, Ph.D.

U.S. Food and Drug Administration

Disclaimer: The views expressed in this presentation are the personal opinions of the speaker and do not necessarily represent the views of FDA

AAPS National Biotech Conference 2010

Overview
Process Analytical Technology (PAT) Freeze-drying Application of PAT in freeze drying Case study Conclusion
2

Process Analytical Technology

A fundamental element of PAT is to increase process understanding and control and to verify product quality prior to release. PAT offers the possibility to increase product quality consistency and to reduce product risk through increased process knowledge and understanding optimized process control with the use of PAT tools
3

Reducing Product Variability

Design Space
Input Raw materials
(or Process Step) Reduced Product Variability

Process

Product (or Intermediate)

Process Variability

Input Process Parameters

Monitoring of Parameters or Attributes

Process Controls/PAT
4 Nasr, FDA

Freeze-Drying
Low-temperature drying process Convert solutions of heat-labile materials into solids Heat and mass transfer

Steps in freeze-drying:
i. Freezing: water converted to ice and the solutes are crystallized or transformed into solid

ii. Primary drying: ice crystals removed by sublimation under vacuum iii. Secondary drying: drying under vacuum where most of the unfrozen water is removed by desorption.
5

Heat Transfer Measurements

Thermocouples Resistance thermal detectors

TEMPRISTM
positioned bottomcenter in the vial -less robust, difficult to handle, sterility problems -Used mainly in laboratory scale wireless battery-free temperature sensors sterilizable and can be used in both laboratory and manufacturing scale optimal comparability of temperature profiles for scale up

+ Reliable, easy to sterilize - size, accurate positioning is difficult, limited validity due to measurement of temperature average primarily in manufacturing scale
6

Pikal et al., 2002; Scheind & Giessler, 2008; Chouvene et al., 2005; Schneid, SP Industries Webinar, 2009

Mass Transfer Measurements

Microbalance

Determines the loss of weight of a sample vial during freeze drying by intermittent or continuous weighing information about sublimation rate and process step endpoints for research and development
Mayeresse & Veillon, 2006; Schneid, SP Industries Webinar, 2009 7

Pressure Measurements
Capacitance Manometer Thermal conductivity sensor (Pirani) Dew point sensor

Independent of the type of gas

Dependent on type of gas, calibrated for a specific gas (usually N2 )

Determination of concentration of water vapor in a gas

8

Roy and Pikal, 1989; Jennings and Duan, 1995; Schneid, SP Industries Webinar, 2009

Pressure Measurements
Mass Spectrometer Plasma emission spectroscopy Manometric Temperature Measurement (MTM)

Measures water vapor, N2 also any additional residual solvents, volatiles, etc

LyotrackTM: Spectroscopic measurement of water concentration in the chamber atmosphere using a cold plasma source connected to the chamber

Pressure Rise Tests are performed periodically by rapid closing (<0.1 s) of the isolation valve between chamber and condenser (laboratory scale)
9

Milton et al., 1997; Tang et al., 2006a; Tang et al., 2006b; Schneid, SP Industries Webinar, 2009

Pressure Measurements
Tunable Diode Laser Absorption Spectroscopy

NIR-spectroscopic method for the determination of trace concentrations of a gas No contact to the product Use in sterile processes (manufacturing) and in all scales of freeze dryers Eg: SMARTTM freeze dryer
www.tdlas.com; Schneid, SP Industries Webinar, 2009 10

Spectroscopic Techniques
Near infra red/Raman Spectroscopy

Near infra-red: for residual moisture measurements in vials through continuous measurements during secondary drying Raman: for determination of physical product characteristics Only one vial monitored for research and development
Brulls et al., 2003;Liu; Bai et al., 2005; Lin & Hsu, 2005, Schneid, SP Industries Webinar, 2009 De Beer et al., 2007; Romero-Torres et al., 2007 11

Tools for Process Development

Fourier Transform Infra Red Spectroscopy Nuclear Magnetic Resonance

Determination of secondary structure and dynamics of proteins during freeze-drying

Kumar, et al., 2009; Bhuyan and Udgaonkar, 1999 12

Tools for Process Development

Freeze-drying microscopy Differential Scanning Calorimetery X-ray Diffraction

LyostatTM

Determination of crystallineDetermination of crtical temperatures amorphous transitions (Collapse/Eutectic) for optimized 13 process Taylor and Zhai, , ;Hatley and Franks, 1991; Pyne and Suryanarayanan, 2001

A Case Study
Use of Near Infra-Red (NIR) to determine moisture content for Freeze-Drying Unit Operation

Design

Analyze

Control

14

Design

Noncontact probes built into the chamber through gaps made in the door of the freeze dryer chamber Placement of sensor depends upon measurement attribute: NIR for residual moisture content and cake quality placed at the bottom of the vial Calibration is set up with various levels of moisture content of the product analyzed with NIR. Calibration can be performed on-line or off-line and validation test samples are also run on the NIR instrument.

15

Analyze
Principal Component Analysis (PCA) to characterize raw materials and process variables

Partial Least Square (PLS) regression to investigate the linkages between spectral information and other sources of data. Sometimes done after pretreatment (2nd derivative or normalization of spectral data)

Y = f{x}+error

Build robust prediction model. Determine accuracy, precision, errors of calibration and prediction 16

Control
Feed incoming data into the computer

Pretreatment of data (if needed) done automatically by chemometric software

Calculate observed Y and compare with expected Y

Continuous feedback control is set

If obtained Y is on target, no need to change operating parameters If outside the range, operating parameters are adjusted

17

Drying Curve
Knowledge space

% water

Design space Operating range

Drying time

18

Summary

Improve process control and deliver more consistent product quality and achieve higher operational efficiency by use of PAT in biotech Freeze-drying process

19

Questions?

Rakhi.shah@fda.hhs.gov

20