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 

  • 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
  • Correlation between molecular dynamics and physical stability of two milled anhydrous sugars: lactose and sucrose
    Correlation between molecular dynamics and physical stability of two milled anhydrous sugars: lactose and sucrose Smith, Geoff; Hussain, Amjad; Bukhari, Nadeem Irfan; Ermolina, I. The process of milling often results in amorphization and the physical stability of amorphous phase is linked with its molecular dynamics. This study focuses on a propensity of two disaccharides (lactose and sucrose) to amorphize on ball milling and the stability of the resultant amorphous phase. The amorphous content in milled sugars is estimated by Differential Scanning Calorimetry (DSC) and the stability was measured in terms of the tendency to recrystallize by Broadband Dielectric Spectroscopy (BDS). The results show that the amorphous content increases with milling time and is greater for lactose than sucrose. At the same degree of amorphization, sucrose recrystallize at temperature ∼15 °C higher than lactose, indicating higher stability. The molecular dynamics (beta relaxation process), suggest that milled sucrose is more stable with higher activation energy (∼9 kJ mol−1) than that of lactose. The moisture content of amorphous phase also impacts its molecular dynamics in terms of increase in activation energy as the moisture decrease with increasing the milling times. The study suggests a greater stability of amorphous sucrose and susceptibility of milled lactose to recrystallize, however, on extended milling when the moisture content decreases, lactose was seen to become relatively more stable. 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.
  • Solubility and dissolution rate enhancement of ibuprofen by co-milling with polymeric excipients
    Solubility and dissolution rate enhancement of ibuprofen by co-milling with polymeric excipients Smith, Geoff; Pedge, Nicholas; Khan, Karrar A; Bukhari, Nadeem Irfan; Hussain, Amjad; Ermolina, I. The aim of this study was to enhance the kinetic solubility and dissolution rate of ibuprofen by co-milling with different excipients and to establish the underlying mechanism(s) for such enhancement. In the first-part, two excipients (HPMC and soluplus) were selected from seven, and the optimal ball-milling parameters of speed and time (18 Hz, 15 min) were determined based on solubility-enhancement and flow-ability criteria. In the second-part, co-milling of different weight-ratios of ibuprofen-to-excipient was carried out and solubility and dissolution rates were determined. Mechanisms of biopharmaceutical enhancement were studied by SEM, laser diffraction, DSC, and FTIR analysis of the co-mixtures. Ibuprofen solubility (0.09 mg/mL for un-milled) was increased by factors of 4–5 and 10–20 for HPMC and soluplus, respectively. The weakening of crystals, stabilization of the amorphous phase and an increase in solid-state hydrogen bonding are the likely mechanisms for this enhancement. Reductions in Q70% dissolution time were also observed, by a factor of 4 and 7 for ibuprofen:HMPC and ibuprofen:soluplus co-milled mixtures, respectively. Although, there were similar reductions in particle size, dispersibility and degree of amorphization in both mixtures, the higher dissolution rate for soluplus, over that for HPMC, must be due to the additional solubilization contribution to the kinetic solubility provided by soluplus. 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.
  • Effect of Arginine on the Aggregation of Protein in Freeze-Dried Formulations Containing Sugars and Polyol: II. BSA Reconstitution and Aggregation
    Effect of Arginine on the Aggregation of Protein in Freeze-Dried Formulations Containing Sugars and Polyol: II. BSA Reconstitution and Aggregation Hackl, E. V.; Darkwah, Joseph; Smith, Geoff; Ermolina, I. The current paper continues our study on the ability of L-arginine to prevent/reduce the aggregation of proteins that results from the various stresses during the lyophilisation and/or storage of lyophilized protein-based products. The first part of our study, i.e. formulation development, was devoted to the rational design and optimization of an L-arginine containing lyophilized formulation which can resist the natural tendency of L-arginine to absorb atmosphere moisture. Mannitol and trehalose were chosen among other excipients to be included in the protein-based formulation, as mannitol in a combination with L-arginine has been shown to reduce moisture sorption while trehalose provides a degree of lyoprotection. In the present study, a number of formulations, which comprised bovine serum albumin (BSA) with and without L-arginine, and with five different ratios of trehalose-to-mannitol (from 30:70 to 80:20) were lyophilised and assessed. The internal structures and the moisture sorption/retention of the lyophilized formulations were characterised. To study the effect of L-arginine on BSA solid-phase stability, the lyophilized powder was exposed to accelerated storage conditions (high moisture (75% RH) and temperature (22 or 45 °C)) for up to 24 h. The lyophilized BSA formulations were then reconstituted and solution-state protein aggregation assessed by turbidimetry at 360 nm and fluorescence spectroscopy using the thioflavin T assay. It was demonstrated that L-arginine can be used in protein-based freeze-dried formulations to significantly reduce the aggregation of protein during the manufacturing, storage and subsequent reconstitution. The results also revealed the importance of a sufficient amount of mannitol in the arginine-containing formulations. 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.
  • The application of dual-electrode through vial impedance spectroscopy for the determination of ice interface temperatures, primary drying rate and vial heat transfer coefficient in lyophilization process development
    The application of dual-electrode through vial impedance spectroscopy for the determination of ice interface temperatures, primary drying rate and vial heat transfer coefficient in lyophilization process development Smith, Geoff; Jeeraruangrattana, Yowwares; Ermolina, I. Through vial impedance spectroscopy (TVIS) is a product non-invasive process analytical technology which exploits the frequency dependence of the complex impedance spectrum of a composite object (i.e. the freeze-drying vial and its contents) in order to track the progression of the freeze-drying cycle. This work demonstrates the use of a dual electrode system, attached to the external surface of a type I glass tubing vial (nominal capacity 10 mL) in the prediction of (i) the ice interface temperatures at the sublimation front and at the base of the vial, and (ii) the primary drying rate. A value for the heat transfer coefficient (for a chamber pressure of 270 µbar) was then calculated from these parameters and shown to be comparable to that published by Tchessalov (2017). 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.
  • Effect of arginine on the aggregation of protein in freeze-dried formulations containing sugars and polyol. 1. Formulation development
    Effect of arginine on the aggregation of protein in freeze-dried formulations containing sugars and polyol. 1. Formulation development Hackl, E. V.; Darkwah, Joseph; Smith, Geoff; Ermolina, I. L-arginine was introduced into protein-based freeze-dried formulations to study the ability of arginine to reduce / prevent from protein aggregation during manufacturing, storage and reconstitution of lyophilized protein-based pharmaceuticals. As L-arginine is known to be very hygroscopic, additional excipients which could provide a moisture buffering capacity need to be introduced into the formulation. In the first part of our study – excipient formulation development – the screening of a number of sugars/polyols has been done in order to select the best combination of excipients that, in a complex with L-arginine, can i) produce freeze-dried cakes with elegant appearance, adequate mechanical properties and reconstitution times, and ii) resist/minimize the moisture sorption. Various freeze-dried cakes containing L-arginine in combination with mannitol, trehalose, lactose, and sucrose were produced and analyzed by TGA, DSC, texture analysis, moisture sorption, cake shrinkage, TVIM and SEM. The non-linear dependencies of the physicochemical properties of the freeze-dried cakes on the sugar-to-mannitol ratios were found. The best combinations of excipients (L-arginine, mannitol and trehalose) were selected to be used in the second part of this work, in which the impact of each selected formulation will be studied in relation to the aggregation of a protein. 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.
  • Micro-structural analysis of tablet surface layers by intelligent laser speckle classification (ILSC) technique: An application in the study of both surface defects and subsurface granule structures
    Micro-structural analysis of tablet surface layers by intelligent laser speckle classification (ILSC) technique: An application in the study of both surface defects and subsurface granule structures Orun, A.; Smith, Geoff Purpose : As a consequence of the latest developments in laser technologies it is now possible to develop a low-cost and accurate tablet inspection system by the unification of optical and artificial intelligence methods. Method: The functionality of the proposed system is based on a sequence of texture analysis of laser speckle images (using laser sources of 650 nm and 808 nm : VIS/IR) followed by the optimization of texture parameters using Bayesian Networks (BN). Results: In the first part of this work, a Bayesian inference method was used to detect micro-scale tablet defects that are generated “progressively” during production whereas in the second part a Bayesian classifier method was used to discriminate between tablets made from different granule sizes. In part two, it was shown that (i) the comparatively higher energy (5mW) IR laser light generates different speckle effects than the lower energy visible (Red 3mW) by interacting with deeper sub-surface of the tablets and (ii) by using multi-classifier systems (MCS) to fuse the Bayesian classifiers from both types of speckle images it was possible to achieve a higher discrimination power (88% classification accuracy) for distinguishing between tablets made from different granule sizes than one can achieve from a single image type. Conclusion: It is suggested that this unified method has the potential to provide for a comprehensive analysis of both tablet quality attributes, on the one hand, and failure modes, on the other, that might be used in the development of a low cost tablet inspection system. 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.
  • Applications for Through Vial Impedance Spectroscopy (TVIS) in Process Parameter Determination
    Applications for Through Vial Impedance Spectroscopy (TVIS) in Process Parameter Determination Smith, Geoff
  • Recent Advances in Through Vial Impedance Spectroscopy (TVIS) for Process Parameter Determination
    Recent Advances in Through Vial Impedance Spectroscopy (TVIS) for Process Parameter Determination Smith, Geoff
  • 3D non-invasive inspection of the skin lesions by close-range and low-cost photogrammetric techniques
    3D non-invasive inspection of the skin lesions by close-range and low-cost photogrammetric techniques Orun, A.; Goodyer, E. N.; Smith, Geoff In dermatology, one of the most common causes of skin abnormality is an unusual change in skin lesion structure which may exhibit very subtle physical deformation of its 3D shape. However the geometrical sensitivity of current cost-effective inspection and measurement methods may not be sufficient to detect such small progressive changes in skin lesion structure at micro-scale. Our proposed method could provide a low-cost, non-invasive solution by a compact system solution to overcome these shortcomings by using close-range photogrammetric imaging techniques to build a 3D surface model for a continuous observation of subtle changes in skin lesions and other features. The main research group is CCI in collaboration with HLS (School of Pharmacy) Open Access article

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

 

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