Manometric Temperature Measurement (MTM) lyophilisation of a challenging clinical trial pharmaceutical

Elliott, Moira A. and Halbert, Gavin W. (2016) Manometric Temperature Measurement (MTM) lyophilisation of a challenging clinical trial pharmaceutical. In: PBP 10th World Meeting in Pharmaceutics, Biopharmeceutics and Pharmaceutical Technology, 2016-04-04 - 2016-04-07, SECC. (Unpublished)

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Abstract

INTRODUCTION Cancer Research UK Formulation Unit The Formulation Unit based at the University of Strathclyde in Glasgow has a research and development history in excess of 25 years, being funded by, and working in partnership with, firstly Cancer Research Campaign, and since 2002, with Cancer Research UK. The Unit is based in an entirely academic University setting, and since 2004 has been licensed by the UK government Medicines and Healthcare products Regulatory Agency (MHRA) for research, development and manufacture of Phase I/II novel small molecule cancer therapeutics and diagnostics. Research programs have delivered new formulations to clinical trial as either sterile or non-sterile presentations. However, the Unit’s specialty is based around small volume parenteral product manufacture. Boronophenylalanine (L-BPA) in Boron Neutron Capture Therapy (BNCT) L-BPA is the premier pharmaceutical selection in BNCT in treatment of selected head and neck tumours. BNCT relies on localisation of boron 10 within a tumour mass, made possible by the amino acid carrier portion of the L-BPA molecule. Phenylalanine is selectively transported across the blood brain barrier and then into astrocytic cells by a LAT-1 transporter system that is up-regulated in tumour. A targeted external neutron beam activates the accumulated L-BPA. In brief, neutron capture by boron causes nuclear re-arrangement and formation of a high linear energy transfer alpha particle and lithium 7 nuclei. Thus the patient is dosed with localised radiotherapy. OLD FORMULATION Issues existed with the previous standard formulation of L-BPA in fructose. L-BPA complexed with fructose has low solubility of around 30mg/mL. Consequently, large administration volumes are required to achieve clinical dosing in tens of grams of drug per patient. Moreover, L-BPA in fructose solutions must be freshly prepared and administered within 48 hours for reasons of product instability (Henriksson et al, 2008). Although rare, hereditary fructose intolerance needs to be considered. Taken together, L-BPA production, preparation and patient dosing is highly challenging. NEW FORMULATION Restrictions The Formulation Unit developed a new improved formulation; the drug product was a lyophilized pH8 solution of L-BPA at 100mg/mL in 110mg/mL mannitol (Schmidt et al, 2011). When lyophilised, a shelf life of 48 months was supported for the drug product. Whilst a three times increase in solubility, and a significantly enhanced product lifetime were worthy formulation enhancements, a new restriction emerged; the solution for lyophilisation contained 21% w/v solids far exceeding the ‘normal’ region of 2% w/v to 5% w/v (Boylan and Nail, 2009). Moreover, the lyophilisation cycle of 6 days was considered commercially unfavourable. A shortened drying cycle of 1 to 3 days would be preferred. Research was therefore initiated to reduce drying cycle time utilising Manometric Temperature Measurement (MTM) technology. MTM Studies MTM controlled freeze drying systems were originally marketed in the first decade of the new millennium. The ability to use software to calculate the performance at the freeze-drying front in real time is scientifically and commercially appealing. The possibility to optimize processing conditions at that same time as data is being received invites the prospect of a reduced experimentation phase thereby rapidly reaching the goal of a maximally efficient freeze drying cycle. In theory, even a minimally experienced operator could achieve this outcome. In summary, MTM functions by taking pressure rise information at regular intervals (Giesler et al, 2007). Based on SMART® software (SP Scientific, Stone Ridge, NY, USA), hourly pressure rise data are taken at a rate of 10 samples per second. The system calculates the product temperature at the sublimation interface and mass transfer resistance of the product. Adjustments are then automatically made to the shelf temperature and system pressure to achieve a calculated target product temperature. The end of primary drying can be determined by comparing the vapour pressure of ice with the system chamber pressure. Input data is minimal, such as vial number, inner vial area, fill volume and weight, concentration, product critical temperature. MATERIALS AND METHODS Chemicals Syntagon AB, Södertälje, Sweden manufactured BPA raw material according to EU current Good Manufacturing Practice (cGMP). D-mannitol (Ph. Eur) was sourced from Sigma-Aldrich, Poole, UK, and fuming hydrochloric acid and sodium hydroxide pellets (both extra pure Ph. Eur., BP, JP, NF) were obtained from VWR International, Lutterworth, UK. Water for Irrigation (WFI) in bulk was acquired from Baxter’s Healthcare Ltd., Norfolk, UK. Type 1 clear glass 50mL vials with 20mm butyl rubber stoppers (proved clean), crimped with 20mm tear off aluminium overseals were all from Adelphi Healthcare Packaging, Haywards Heath, UK. Lyophilisation equipment MTM software (SMART®) was operated on an FTS Systems Lyostar II drier (Biopharma, Winchester, UK). CONCLUSION A new improved L-BPA formulation in mannitol has been developed and used in human clinical trial. Further research using MTM technology succeeded in reducing a 6 day drug product drying cycle to 53 hours. The formulation exhibited non-ideal behaviour, and MTM failed to predict drying parameters, e.g., base of vial temperature, that are more closely replicated in ‘ideal’ test articles such as a 5% mannitol comparator. Further test lyophilisations are required to reach ideal. ACKNOWLEDGMENTS This research is funded by Cancer Research UK. REFERENCES 1. Boylan, J.C. and Nail, S.L. Parenteral Products, in: Florence, A.T. and Siepman, J. (Eds.), Modern Pharmaceutics. Informa Healthcare, New York, 565-609 (2009). 2. Giesler, H.; Kramer, T. and Pikal, M. J. Use of manometric temperature measurement (MTM) and SMART freeze dryer technology for development of an optimised freeze drying cycle. J. Pharm Sci. 96(12), 3402-3418 (2007). 3. Henriksson, R.; Capala, J.; Michanek, A.; Lindahl, S.A.; Satford, L.G.; Franzen, L.; Blomquist, E.; Westlin, J.E. and Bergenheim, A.T. Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA). Radiotherapy and Oncology 88, 183-191 (2008). 4. Schmidt, E.; Dooley, N.; Ford, S. J.; Elliott, M. and Halbert, G. W. Physicochemical investigation of the influence of saccharide based parenteral formulation excipients on L-p-boronphenylalanine solubilisation for Boron Neutron Capture Therapy. J. Pharm. Sci. 101(1), 223-232 (2011).

ORCID iDs

Elliott, Moira A. ORCID logoORCID: https://orcid.org/0000-0002-9964-5671 and Halbert, Gavin W.;
CORE (COnnecting REpositories)