pat in freeze drying

7/27/2019 PAT in Freeze Drying

1/20

1

Application of PAT in Freeze-Drying of Biopharmaceuticals

Rakhi B. Shah, Ph.D .U.S. Food and Drug Administration

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

AAPS National Biotech Conference 2010


2/20

2

Overview

Process Analytical Technology (PAT)

Freeze-drying

Application of PAT in freeze drying

Case study

Conclusion


3/20

3

Process Analytical Technology

A fundamental element of PAT is to increaseprocess understanding and control and to verifyproduct quality prior to release.

PAT offers the possibility to increase productquality consistency and to reduce product riskthrough increased process knowledge andunderstanding optimized process control with theuse of PAT tools


4/20

4

Reducing Product Variability

Process(or Process Step)

DesignSpace

Monitoring of Parametersor Attributes

Process Controls/PAT

InputProcess

Parameters

InputRaw materials

Product(or Intermediate)

ProductVariability

ReducedProductVariability

ProcessVariability

Nasr, FDA


5/20

5

Freeze-DryingLow-temperature drying process

Convert solut ions of heat-labile materials into sol ids

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 theunfrozen water is removed by desorption.


6/20

6

Heat Transfer MeasurementsThermocouples

positioned bottom-center in the vial

-less robust ,difficult tohandle , sterilityproblems-Used mainly inlaboratory scale

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

wireless battery-freetemperature sensors

sterilizable and can be usedin both laboratory andmanufacturing scale optimal comparability of temperature profi les for scale up

Resistance thermaldetectors

TEMPRIS TM+ Reliable, easy tosterilize- s ize , accuratepositioning is difficult,limited validity due tomeasurement of temperature averageprimarily inmanufacturing scale


7/20

7

Mass Transfer MeasurementsMicrobalance

Determines the loss of weight of a sample vial during freeze drying byintermittent or continuous weighing information about sublimationrate and process step endpoints

for research and development

Mayeresse & Veillon, 2006; Schneid, SP Industries Webinar, 2009


8/20

8

Pressure MeasurementsCapacitance Manometer Thermal conductivity

sensor (Pirani)

Independent of the type of gas

Dependent on type of gas, calibrated for aspecific gas (usuallyN2 )

Dew point sensor

Determinationof concentrationof water vapor in a gas

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


9/20

9

Mass Spectrometer Plasma emissionspectroscopy

Measures water vapor, N2 alsoany additionalresidualsolvents,volatil es, etc

Lyotrack TM:Spectroscopicmeasurement of water concentration in thechamber atmosphereusing a cold plasmasource connected to thechamber

Manometric TemperatureMeasurement (MTM)

Pressure Rise Testsare performedperiodically by rapidclosing (


10/20

10

Tunable Diode Laser Absorption Spectroscopy

NIR-spectroscopic method for the determination of trace concentrations of a gasNo contact to the product

Use in sterile processes (manufacturing) and in all scales of freeze dryers

Eg: SMART TM freeze dryer

www.tdlas.com ; Schneid, SP Industries Webinar, 2009

Pressure Measurements


11/20

11

Spectroscopic Techniques

Near infra-red: for residual moisture measurements in vials throughcontinuous measurements dur ing secondary drying

Raman: for determination of physical product characteristi cs

Only one vial monitoredfor research and development

Near infra red/Raman Spectroscopy

Brulls et al., 2003;Liu; Bai et al., 2005; Lin & Hsu, 2005, Schneid, SP Industries Webinar, 2009De Beer et al., 2007; Romero-Torres et al., 2007


12/20

12

Tools for Process DevelopmentFourier Transform Infra Red Spectroscopy Nuclear Magnet ic Resonance

Determination of secondary structure anddynamics of proteins during f reeze-drying

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


13/20

13

Tools for Process DevelopmentFreeze-drying microscopy

Lyostat TM

Differential ScanningCalorimetery

X-ray Diffraction

Determination of crtical temperatures(Collapse/Eutectic) for opt imized

process

Determination of crystalline-amorphous transitions

Taylor and Zhai, , ;Hatley and Franks, 1991; Pyne and Suryanarayanan, 2001


14/20

14

A Case Study

Use of Near Infra-Red (NIR) to determine moisturecontent for Freeze-Drying Unit Operation

Design

Analyze Control


15/20

15

Design

Noncontact probes buil t into the chamber through gaps made in the door of the freeze dryer chamber

Placement of sensor depends upon measurement attr ibute: NIR for residual moisture content and cake quality placed at the bottomof the vial

Calibration is set up with various levels of mois ture content of the productanalyzed with NIR. Calibration can be performed on-line or off-line andvalidation test samples are also run on the NIR instrument.


16/20

16

Analyze

Principal Component Analysis (PCA) tocharacterize raw materials and processvariables

Parti al Least Square (PLS) regression toinvestigate the linkages betweenspectral information and other sourcesof data. Sometimes done after pretreatment (2 nd derivative or normalization of spectral data)

Build robust prediction model.Determine accuracy, precis ion, errors of

calibration and prediction

Y = f{x}+error


17/20

17

ControlFeed 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 parametersIf outside the range, operating parameters are adjusted


18/20

18

Drying Curve

Drying time

% w

a t e r

Design space

Knowledge space

Operating range


19/20

19

Summary

Improve process control and deliver more consistentproduct quality and achieve higher operationalefficiency by use of PAT in biotech Freeze-dryingprocess


20/20

20

Questions?

[email protected]

pat in freeze drying

Documents