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Professor Geoff Smith

Job: Professor of Pharmaceutical Process Analytical Technology

Faculty: Health and Life Sciences

School/department: Leicester School of Pharmacy

Research group(s): Pharmaceutical Technologies

Address: De Montfort University, The Gateway, Leicester, LE1 9BH.

T: +44 (0)116 250 6298

E: gsmith02@dmu.ac.uk

W: www.dmu.ac.uk/pharmaceutical

Social Media: uk.linkedin.com/in/gsmith02

 

Personal profile

Geoff Smith graduated in Pharmacy from the University of Bath in 1985 and obtained his PhD from the University of Brighton in 1991 based on a study of the mechanisms of action of cryoprotectants. It was then that he developed a keen interest in the dielectric properties of materials.

He joined De Montfort University in 1993 and went on to develop a number of lines of research based around broad band dielectric measurements. In recent years these studies are focussed increasingly on PAT applications in process development and manufacturing controls for the pharmaceutical industry. His research group is now working on a number of pharmaceutical applications for impedance, dielectric and terahertz spectroscopy alongside optical techniques such as laser speckle and optical flow. These techniques cover an extremely wide range of frequencies thereby enabling the direct analysis of material properties over a wide range of scales from the macroscopic to the molecular.

He was responsible for the development of through-vial impedance spectroscopy (LyoDEA) as a PAT tool for monitoring phase behaviour (ice formation and eutectics), temperatures, and drying profiles and end points, in collaboration with GEA Pharma Systems and AstraZeneca (Funded by the Technology Strategy Board).

More recently his pharmaceutical research focus has extended to investigations into the use of electrostatic noise measurements and optical imaging for applications in roller compaction, powder flow and tablet defect analysis, with the aim of improving understanding and control of tablet production methods.

From 2007 he began to re-structure the Pharmaceutical Technologies group, by recruiting staff from various backgrounds, including chemists, physicists, chemical engineers and process control specialists in order to diversify the research base of the group and to re-focus efforts on current pharmaceutical industry challenges in product design and manufacturing. By 2010 he had instigated De Montfort University's Pharmaceutical Quality by Design programme, with a wide range of industrial practitioners providing webinars on elements of quality by design.

 

Research group affiliations

Pharmaceutical Technologies 

Publications and outputs

  • Determination of ice interface temperature, sublimation rate and the dried product resistance, and its application in the assessment of microcollapse using through-vial impedance spectroscopy
    Determination of ice interface temperature, sublimation rate and the dried product resistance, and its application in the assessment of microcollapse using through-vial impedance spectroscopy Smith, Geoff; Jeeraruangrattana, Yowwares; Polygalov, E.; Ermolina, I. Through-vial impedance spectroscopy (TVIS) is a new approach for characterizing product attributes during freeze-drying process development. In this study, a pair of copper foil electrodes was attached to the external surface of a Type I glass tubing vial, of nominal capacity 10 mL and containing 3.5 g of an aqueous solution of 5% w/v lactose, and the impedance spectrum of the vial and contents recorded during a lyophilization cycle. The cycle included a temperature ramp in the primary drying stage in order to induce a collapse event in the dry layer. Using the peak in the dielectric loss spectrum, associated with the dielectric relaxation of ice, methods were developed to predict the sublimation rate and the ice interface temperature at the sublimation front, from which the dry layer resistance was then calculated. A four-fold increase in sublimation rate and a reduction in the dry layer resistance wereobserved once the ice interface temperature reached −33 °C, which coincides with the onset of the glass transition (as determined by DSC) and the time point at which micro-collapse occurred (as evidenced by SEM images at the end of the cycle). This work suggests a prospective application of impedance measurements in driving process efficiencies by operating the dryer at the highest achievable temperature (i.e. the collapse temperature) whilst avoiding macro-collapse. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • An investigation on a quantum communication phenomenon between sub-atomic properties of substances by Quantum eraser pattern quantification
    An investigation on a quantum communication phenomenon between sub-atomic properties of substances by Quantum eraser pattern quantification Orun, A.; Smith, Geoff The proposed novel idea is concerned with the investigation on a probability of sub-atomic quantum communication between the chemical substances by use of “interferometric Quantum eraser” pattern analysis, which would be the first step towards the further comprehensive study on a similar natural communications between the medications and diseased organic tissues. The hypothesis is based on the idea that, sub-atomic particles like photons attempt to access or gain complementary information causing their “wave-particle duality” shifting which is used to observe their time-sequenced activities. Such information would probably be provided by sub-atomic quantum communication action demonstrated between the substances in a chemical reaction. Similarly, the medications may have curing effects on a diseased organic tissue after such “natural” communication, by which a complementary information is transferred from the sub-atomic properties of chemical substance to the diseased organic tissue at same level for the treatment. The file attached to this record is the author's final peer reviewed version.
  • Through-Vial Impedance Spectroscopy (TVIS): A New Method for Determining the Ice Nucleation Temperature and the Solidification End Point
    Through-Vial Impedance Spectroscopy (TVIS): A New Method for Determining the Ice Nucleation Temperature and the Solidification End Point Smith, Geoff; Jeeraruangrattana, Yowwares The file attached to this record is the author's final peer reviewed version.
  • The use of through vial impedance spectroscopy (TVIS) for determination of ice nucleation, solidification end point, and mannitol crystallization during freezing and re-heating
    The use of through vial impedance spectroscopy (TVIS) for determination of ice nucleation, solidification end point, and mannitol crystallization during freezing and re-heating Ogugua, Longinus; Smith, Geoff; Orun, A. This is a study of the freezing/reheating behavior of aqueous solutions of mannitol with respect to lyophilization process development given the prevalent use of the excipient. Here, through-vial impedance spectroscopy (TVIS) was used to study the thermophysical kinetics of an aqueous solution of 5%w/v mannitol during a freezing and re-heating phase of a freeze-drying cycle. Temperature calibration of the TVIS parameter FPEAK enabled the determination of the ice nucleation temperature Tn at −13 oC while the ice solidification end point was observed based on the time profile of C' (0.2MHz), i.e. the real part capacitance at 0.2 MHz. A time difference of 20 min between the onset and end point then defines the ice solidification time ti. A later step in C' (0.2MHz) indicated that mannitol crystallized at -32 oC and 20 minutes from end of ice solidification. Upon reheating at 0.2 oC/min, a large increase in C' (0.2MHz) was seen at −32 oC indicating the onset of melting of mannitol crystals which then lasted 20 min.
  • Application of through vial impedance spectroscopy (TVIS) for the determination of ice nucleation, solidification endpoint, and mannitol crystallization and melt-back temperature during freezing and annealing
    Application of through vial impedance spectroscopy (TVIS) for the determination of ice nucleation, solidification endpoint, and mannitol crystallization and melt-back temperature during freezing and annealing Ogugua, Longinus; Smith, Geoff; Orun, A. Studies of the freezing behavior of aqueous solutions of mannitol are highly relevant to lyophilization process development given the prevalent use of this excipient. Here, through-vial impedance spectroscopy (TVIS) was used to study the behaviour of an aqueous solution of 5%w/v mannitol during a freezing and re-heating cycle. Temperature calibration of the TVIS parameter FPEAK enabled the determination of the ice nucleation temperature Tn at −13 oC while the ice solidification end point was observed based on the time profile of C' (0.2MHz), i.e. the real part capacitance at 0.2 MHz. A time difference of 20 min between the onset and end point then defines the ice solidification time ti. A later step in C^' (0.2MHz) indicated that mannitol crystallized at -32 oC and 20 minutes from end of ice solidification. Upon reheating at 0.2 oC/min, a large increase in C' (0.2MHz) was seen at −32 oC indicating the onset of melting of mannitol crystals which then lasted 20 min.
  • Through vial impedance spectroscopy (TVIS): A novel approach to process understanding for freeze-drying cycle development
    Through vial impedance spectroscopy (TVIS): A novel approach to process understanding for freeze-drying cycle development Smith, Geoff; Polygalov, E. Through vial impedance spectroscopy (TVIS) provides a new process analytical technology for monitoring a development scale lyophilization process, which exploits the changes in the bulk electrical properties that occur on freezing and subsequent drying of a drug solution. Unlike the majority of uses of impedance spectroscopy, for freeze-drying process development, the electrodes do not contact the product but are attached to the outside of the glass vial which is used to contain the product to provide a non-sample-invasive monitoring technology. Impedance spectra (in frequency range 10 Hz to 1 MHz) are generated throughout the drying cycle by a specially designed impedance spectrometer based on a 1 GΩ trans-impedance amplifier and then displayed in terms of complex capacitance. Typical capacitance spectra have one or two peaks in the imaginary capacitance (i.e., the dielectric loss) and the same number of steps in the real part capacitance (i.e., the dielectric permittivity). This chapter explores the underlying mechanisms that are responsible for these dielectric processes, i.e., the Maxwell-Wagner (space charge) polarization of the glass wall of the vial through the contents of the vial when in the liquid state, and the dielectric relaxation of ice when in the frozen state. In future work, it will be demonstrated how to measure product temperature and drying rates within single vials and multiple (clusters) of vials, from which other critical process parameters, such as heat transfer coefficient and dry layer resistance, may be determined. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Side by Side Layers Freeze Dried Orally Disintegrating Tablets
    Side by Side Layers Freeze Dried Orally Disintegrating Tablets Abdullah, A.; Smith, Geoff This study aimed to develop methodologies for the fabrication and testing of side by side layers freeze dried (lyophilized) orally disintegrating tablets (ODT) for same or different phase formulation. These side by side layers tablets will provide opportunities for combination therapies for patients who experience swallowing difficulty (e.g. geriatrics and paediatrics) and might enhance the bioavailability and incompatibility of some drugs. Two different solutions (A and B) were prepared separately and each solution was to create a different formulated layer to obtain different release profiles. The first layer was fabricated by injecting the solution A to an empty tablet blister to the half and freezing at -80°C for one hour in an external freezer. After the first layer was completely frozen, the solution B was injected into the rest half of the tablet blister and frozen at -80°C for one hour in an external freezer to create the second layer. Then, frozen side by side layers tablet was freeze dried and the resulting multilayer tablets were investigated. The study has shown that side by side layers freeze dried orally disintegrating tablets can be fabricated and formulated for same or different phase and with different disintegrating time for each layer to provide different release profiles. The optimization of adhesion between layers is required. The study has also shown that concentrations of gelatin and mannitol can affect the formulation characteristics. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the URI link. Open access journal
  • Application of Impedance Based Technology to investigate the Collapse of Freeze-dried Sugar-salt Solutions
    Application of Impedance Based Technology to investigate the Collapse of Freeze-dried Sugar-salt Solutions Jeeraruangrattana, Y.; Polygalov, E.; Ermolina, I.; Smith, Geoff
  • Application of through vial impedance spectroscopy to different containers
    Application of through vial impedance spectroscopy to different containers Vadesa, A.; Smith, Geoff; Polygalov, E.; Horley, Neill; Dalby, Paul
  • Application of Through Vial Impedance Spectroscopy for Lyophilization Process Development
    Application of Through Vial Impedance Spectroscopy for Lyophilization Process Development Pandya, Bhaskar; Smith, Geoff; Polygalov, E.; Ermolina, I.

Click here for a full list of Geoff Smith's publications and outputs.

Key research outputs

Smith, G., Arshad, M.S., Polygalov, E., Ermolina, I., McCoy, T.R., Matejtschuk, P. (2017). Process Understanding in Freeze-Drying Cycle Development: Applications for Through-Vial Impedance Spectroscopy (TVIS) in Mini-pilot Studies. Journal of Pharmaceutical Innovation, 12 (1), pp. 26-40

Arshad, M.S., Smith, G., Polygalov, E., Ermolina, I. (2014). Through-vial impedance spectroscopy of critical events during the freezing stage of the lyophilization cycle: The example of the impact of sucrose on the crystallization of mannitol. European Journal of Pharmaceutics and Biopharmaceutics, 87 (3), pp. 598-605

Smith, G., Polygalov, E., Arshad, M.S., Page, T., Taylor, J., Ermolina, I. (2013) An impedance-based process analytical technology for monitoring the lyophilisation process. International Journal of Pharmaceutics, 449 (1-2), pp. 72-83

Smith, G., Arshad, M.A., Polygalov, E., Irina Ermolina, I. (2013) Factors Affecting the Use of Impedance Spectroscopy in the Characterisation of the Freezing Stage of the Lyophilisation Process: the Impact of Liquid Fill Height in Relation to Electrode Geometry. AAPS PharmSciTech, online first

Smith, G., Arshad, M.S., Polygalov, E. and Ermolina, I. (2013) An application for impedance spectroscopy in the characterisation of the glass transition during the lyophilization cycle: The example of a 10% w/v maltodextrin solution. European Journal of Pharmaceutics and Biopharmaceutics, 86 (3 Part B), pp. 1130-1140

Smith, G., Polygalov, E. & Page, T. (2011) A method for monitoring and/or controlling process parameters of a lyophilisation process. British patent application 2480299. Application Number 1007961.4. Filing date 12.05.2010

Research interests/expertise

  • Freeze-drying process development
  • Process analytical technologies (novel sensors in process understanding and control)
  • Impedance spectroscopy, dielectric spectroscopy, terahertz spectroscopy and terahertz imaging, dynamic laser speckle, electrostatic measuremnst of powder flow
  • See current PhD projects for more information.

Areas of teaching

  • Pharmaceutical Sciences
  • Good Manufacturing Practice
  • Pharmaceutical Quality by Design
  • Freeze-Drying
  • Preformulation

Qualifications

  • PhD. Mechanims of Action of Cryoprotectant 1991
  • BPharm 1985 University of Bath

Courses taught

  • BSc Pharmaceutical and Cosmetic Sciences
  • MSc Pharmaceutical Quality by Design

Membership of external committees

 

Membership of professional associations and societies

 

Forthcoming events

 

Conference attendance

Smith   G. (2018) Through-Vial Impedance Spectroscopy (TVIS). A new process   analytical technology for freeze-drying process development. Podium   presentation at: SMi 6th Annual Conference on Pharmaceutical Freeze-Drying   Technology, 2018 June 13-14th, Holiday Inn Kensington Forum, London, United   Kingdom 
Smith G. (2018) Through-Vial Impedance Spectroscopy (TVIS). A   Novel Process Analytical Technology for the Development of Pharmaceutical   Products and Processes.Podium presentation at 2nd Annual Lyophilization   Summit, Vienna, Austria, May 24-25th 2018
Smith   G. (2018) Through Vial Impedance Spectroscopy (TVIS): Dual-Electrode System   for Process Parameter Determination. Podium presentation at  ISL-FD Midwest Chapter Annual Meeting,   Midwest Conference Centre, Northlake, IL 60164, USA, April 12th 2018
Smith   G. Through Vial Impedance Spectroscopy (TVIS): A Novel Approach in the   Development of Freeze-Drying Processes for Drug Products. Podium presentation   at 10th International Workshop on Impedance Spectroscopy, 2017 September   27-29, Chemnitz, Germany
Smith,   G. (2017) Recent Advances in Through Vial Impedance Spectroscopy (TVIS) for   Process Parameter Determination. ISL-FD Conference April 26-28th 2017.   Havana, Cuba
Smith,   G. (2017) Applications for Through Vial Impedance Spectroscopy (TVIS) in   Process Parameter Determination. LyoTalk Dublin, May 22 2017
Smith, G. (2016)  The   Application of Through Vial Impedance Spectroscopy (TVIS)  for Process Parameter Determination in   Freeze-Drying Method Development. PDA Europe. Pharmaceutical Freeze Drying   Technology. Strasbourg, 27 – 28 September 2016
Smith, G. (2016) Through Vial Impedance Spectroscopy. SMi   Lyophilisation Europe, Kensington, London, United Kingdom 4-5 July 2016
Smith, G. (2015) Process Analytical Technology and the Question   of Scale. ISL-FD 2015 International Society of Lyophilization – Freeze Drying   Conference and Seminar. College of Pharmacy, Barcelona, 8-10 July 2015
Smith, G. (2015) A focus on PAT in freeze-drying. APS Parenteral   Focus Group meeting on Freeze Drying and Alternative Drying Technologies for   Parenterals, Burleigh Court, Loughborough University.28 January 2015

Consultancy work

We currently offer our expertise in freeze-drying process development to assist pharmaceutical companies in the development of optimized freeze-drying cycles. Through the application of new process analytical technologies (LyoDEA) we can reduce your development time while delivering a shorter cycle time.

This will reduce the materials consumed in development, accelerate your product to market, and provide you with a more efficient process hence reduce the cost of manufacture.

Externally funded research grants information

EXTALcoat : External Lubrication Coating Inspection System by Dynamic Laser Speckle Imaging (grant ref. 132872)

£115,054 Feasibility Study

March 1 2018 to  February 28 2019

Funding body : Innovate UK

Partners: Gasfill Ltd (Micron Design), Nutrapharma, Merlin Powder Characterization, S3 Process, De Montfort University

 

FastLyo (grant ref. 133425)

£99,849 Feasibility Study

March 1 2018 to  February 28 2019

Funding body : Innovate UK

Partners: Biopharma Process Solutions, OnkoLytika, De Montfort University

 

AtlasBio (grant ref. 102610)

£803 846 Collaborative R&D

February 1 2017 to  January 31 2020

Funding body : Innovate UK

Partners: GEA, BlueFrog, CPI, 

OnkoLytika, IS Instruments, Ocean Optics,

National Institute for Biological Standards and Control, Nottingham University, De Montfort University

 

BioStaRT (grant ref. 101711)

£367 567 Collaborative R&D

August 1 2014 to Jan 31 2018

Funding body : Innovate UK

Partners: GEA, BlueFrog, Sanofi (Ireland)

National Institute for Biological Standards and Control, De Montfort University    

 

LyoDEA (grant ref. 100527)

£217 160 Collaborative R&D

November 1 2008 to October 31  2012

Funding body : Technology Strategy Board

Partners: GEA, AstraZeneca, Ametek, De Montfort University

Published patents

Smith, G, and Polygalov E. (2007). Apparatus for measuring the dielectric properties of conductive materials. British patent 0704880.4 Filing date 13 March 2007. Publication number GB2447477 17 September 2008

Smith, G., Polygalov, E. and Page, T. (2011) A method for monitoring and/or controlling process parameters of a lyophilisation process. GB patent GB2480299 (A). Application number GB20100007961 20100512. Priority date 12 May 2010. Published 16th November 2011

TVIS : Through Vial Impedanace Spectroscopy

The freeze-drying cycle comprise three stages, of pre-freezing (to form ice and to crystallise out any solutes with a propensity to crystallise), primary drying to remove the ice phase, and secondary drying to remove the water which is physic-sorbed to the remaining matrix or crystalline and amorphous solids. Process optimization and scale up requires measurement technologies for characterising each stage of the process. In the freezing stage, it is essential to maximise the amount of ice that forms and to optimise the ice structure in order to facilitate sublimation in the primary drying phase. In primary drying it is essential that the product temperature is as high to reduce the drying time, while maintaining it below certain critical temperatures (e.g. eutectic temperature if the unfrozen phase is largely crystalline and the glass transition if the unfrozen phase is largely amorphous) in order to avoid collapse (from melting and/or loss of structural viscosity.

Process analytical techniques for achieving these challenges goals are limited. Thermocouples are used primary for the detection of crystallization (primary phase transitions) but are ineffective at detecting the glass transition and collapse. Pressure rise testing is used in primary drying, and through modelling of the system can be used to control the temperature at the sublimation interface, and hence optimise the drying process. However, the thermocouple is invasive and may itself alter the ice crystal structure (and hence drying profile), whereas the pressure rise testing model relies on many assumptions in the model which provides an average batch measurement across the drier, and only works in the early phase of drying when there is a steady state condition.

The Pharmaceutical Technologies Group has developed a new approach for process understanding for freeze-drying cycle development, which uses a through vial impedance measurement (TVIS) to characterise a broad range of features of the process, including, ice onset times, the completion of ice solidification, the glass transition, and the structural relaxation of the unfrozen solid, and the primary drying rate and end point. The on-going development of this technology will see the application with micro-titre plate technologies for formulation screening (micro-scale down) and for scale up into production by using a non-contact probes for monitoring problematic regions within the drier.

 Key References

Arshad, M.S. Smith, G., Polygalov, E., Ermolina, I. (2014). Through-vial impedance spectroscopy of critical events during the freezing stage of the lyophilization cycle: The example of the impact of sucrose on the crystallization of mannitol. Eur J Pharm Biopharm., 87, (3), pp. 598-605

Smith, G.; Arshad, Muhammad Sohail; Polygalov, E., Ermolina, I. (2014). Through-Vial Impedance Spectroscopy of the Mechanisms of Annealing in the Freeze-Drying of Maltodextrin: The Impact of Annealing Hold Time and Temperature on the Primary Drying Rate. J Pharm. Sci., 103, (6), 1799-1810

Smith, G., Arshad, M.A., Polygalov, E., Ermolina, I. (2013) Factors Affecting the Use of Impedance Spectroscopy in the Characterisation of the Freezing Stage of the Lyophilisation Process: the Impact of Liquid Fill Height in Relation to Electrode Geometry. AAPS PharmSciTech, online first

Smith, G., Arshad, M.S., Polygalov, E. and Ermolina, I. (2013) An application for impedance spectroscopy in the characterisation of the glass transition during the lyophilization cycle: The example of a 10% w/v maltodextrin solution. European Journal of Pharmaceutics and Biopharmaceutics, 86 (3 Part B), pp. 1130-1140

Smith, G., Polygalov, E., Arshad, M.S., Page, T., Taylor, J., Ermolina, I.  (2013) An impedance-based process analytical technology for monitoring the lyophilisation process. International Journal of Pharmaceutics, 449 (1-2), pp. 72-83

Smith, G., Arshad, M.S., Polygalov, E. and Ermolina, I. (2013) An application for impedance spectroscopy in the characterisation of the glass transition during the lyophilization cycle: The example of a 10% w/v maltodextrin solution. European Journal of Pharmaceutics and Biopharmaceutics, 86 (3 Part B), pp. 1130-1140

Smith, G., Polygalov, E. & Page, T. (2011) A method for monitoring and/or controlling process parameters of a lyophilisation process. British patent application 2480299. Application Number 1007961.4. Filing date 12.05.2010