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

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)

The gut in the beaker : missing the surfactants

Gastrointestinal drug administration is the preferred route for the majority of drugs however, the natural physiology and physicochemistry of the gastrointestinal tract is critical to absorption but complex and influenced by factors such as diet or disease. The pharmaceutical sciences drive for product consistency has led to the development of in vitro product performance tests whose utility and interpretation is hindered by the complexity, variability and a lack of understanding. This article explores some of these issues with respect to the drug, formulation and the presence of surfactant excipients and how these interact with the natural bile salt surfactants. Interactions start in the mouth and during swallowing but the stomach and small intestine present the major challenges related to drug dissolution, solubility, the impact of surfactants and supersaturation along with precipitation. The behaviour of lipid based formulations and the influence of surfactant excipients is explored along with the difficulties of translating in vitro results to in vivo performance. Possible future research areas are highlighted with the conclusion that, “a great deal of work using modern methods is still required to clarify the situation”

An investigation into fused filament fabrication for pharmaceutical manufacturing

In a modern world, what is the best way to deliver medicines to the patient? Human beings are an extremely diverse species with many different factors that can influence the behaviour of a drug within the body. Children are a perfect example of such variety. Doses are often prescribed based on body weight, and can vary greatly from infants to adolescents. With current ‘traditional’ manufacture of oral dose pharmaceuticals, generally only a limited number of doses are produced, leading to difficulties with appropriate dosing. The ability to manufacture personalised doses for these patients would be of great benefit both practically and financially, and may even lead to ‘point of care’ manufacture

Inkjet printing of oral dosage forms to solubilize BCS Class II drugs

Oral drug delivery remains the preferred method of administration but BCS Class II drugs are not ideally suited to this due to their inherent poor solubility. Although a number of methods to increase solubility already exist, there is a need for less damaging methods of production which are more flexible to the needs of the patient. The innovative formulation method of inkjet printing has been suggested for this purpose as it has the capacity to produce highly precise dosing in a continuous manner. The Optomec Aerosol Jet 200 Printer utilised in the current study has never been used in pharmaceutical research before and it is highly interesting as it functions in a manner akin to a miniaturised spray dryer. Due to the low dose content of a single layer, formulations can be easily tailored to the patient’s individual requirements by changing the size and speed of deposition, utilising different nozzle sizes and layering to increase the overall dose. Raman spectroscopy, scanning electron microscopy and powder x-ray diffraction suggest that printing the drug alone results in a crystalline product. However, in the presence of a polymer it seems to form a less crystalline product suggesting the polymer is promoting solid dispersion formation in a similar manner to a spray dryer. Completely amorphous formulations are achieved on application of a premixed "ink" with a polymer content of 75% or more, allowing up to 25% drug loading. Drug release increases 10-fold on printing relative to a comparable powder blend and thus inkjet printing can be considered to be a viable method of improving the overall performance of the drug. The next steps will be to utilize this established methodology to produce innovative controlled release on a small scale

Inkjet printing oral dosage forms

The current study aims to establish an innovative method of effectively solubilising Biopharmaceutical Classification System Class II drugs using inkjet printing. Dosage forms have been produced using an Optomec AJ200 3D Inkjet printer. Printing with an appropriate polymer seems to result in an amorphous product, which will hopefully have a greater overall solubility

Printability of pharmaceutical polymers in FDM 3D printers

3D printing (3DP) of pharmaceutical formulations via commercially available FDM printers has gained interested in recent years, enabling personalisation of medicines. It also facilitates advanced control of the micro-structure of the tablet core, permitting fine tuning of product release characteristics with a single formulation. In addition, the technology also offers a platform for Dose escalation studies employing a single formulation and single manufacturing step. The objective of this study was to develop a printability map of pharmaceutically relevant feedstock material for FDM

Solid dispersions : improving drug performance through tablet micro-structure design

Purpose Solid dispersions formulations manufactured by Hot-Melt-Extrusion (HME) have shown to improve drug release for BCS class II drugs, such as Mefenamic acid (MFA). Drug release for MFA is highly dependent on particle size. Commercially available MFA capsules have shown high variability in their drug release profile which may lead to variable efficacy. This study shows how solid dispersion formulations and microstructure design significantly improve product performance. Methods Solid dispersion formulation of 50% w/w Mefenamic acid (MFA, Sigma Aldrich) and Soluplus (BASF) containing 15% w/w Sorbitol (Merck) as plasticiser (SOL15) was prepared by HME (Process 11, Thermofisher). The formulation was a) pelletised and hand filled into size 0 hard gelatine capsules and b) 3D printed (3DP) with a porous core exposed to the surface (Figure 1) to achieve a MFA dose of 250mg. Neat MFA powder and a physical mixture (PM) of 50% (w/w) MFA and SOL15 powder were also hand filled into size 0 hard gelatine capsules to generate a MFA dose of 250mg. Pellets were prepared by cutting the HME filament (~2 mm diameter) to the length of approximately ~2mm. The 3DP tablets were printed with a novel in-house designed integrated HME-3D printer (Intellectual Property Office UK, patent application number 2101534.2). The 3D printed tablet shape was elliptical with a length of 22 mm, width of 12 mm and height of 5mm. The Infill % was set to 47.3%, which equated to an infill line distance of 0.85 mm (gap between infill lines). No top or bottom layer were printed to create a porous tablet core. Drug release profiles of all three formulations were established by performing a Dissolution test based on USP 37 of Mefenamic acid capsules (n=6) in Tris buffer pH 9 and UV analysis. The % drug release (normalised to tablet weight) was calculated and reported. Results Whilst MFA powder achieved a very consistent released, it failed to release >85 % content within 60 minutes (Figure 2A). The physical mixture showed greater variation between the 6 tablets, but released >85% content at 55 minutes. The pelletised solid dispersion formulation significantly improved drug release compared to neat MFA powder and the PM, >85% drug release within 35 minutes and therefore complying with pharmacopeial release requirements (>85% at 45 minutes) (Figure 2B). The variation between individual tablets was also lower compared to the PM. The 3DP tablet, with a highly controlled microstructure, achieved complete drug release at 20 minutes (91.6%). The variation in drug release was very high at 10 minutes only and very low at all other data points. Conclusions Solid dispersion formulation significantly improved the drug release profile by increasing the consistency and reducing the time to achieve complete drug release (>85%) to 35 minutes and 20 minutes for the 3DP tablet. This demonstrates the possibility of fine tuning drug release profiles through micro-structure control by 3DP

Identifying the operating space and repeatability of a novel filament free FDM printer

Purpose -- Processing solid dispersion filament feedstock materials by Fused Deposition Modelling (FDM) have shown to facilitate control of drug release profiles through micro-structure design. The mechanical and rheological properties of many feedstock materials, particularly immediate release polymers, are not suitable for processing in a conventional FDM 3D printer. This study shows the operational space and performance of a novel non-filament based FDM printer, overcoming these material-based limitations. Conclusions -- Operational limits, in terms of rheological properties of formulations, have been identified for this novel non-filament FDM printer. Repeatability of tablet prints showed good uniformity of mass, complying with pharmacopeial specifications for oral solid dose forms

Mechanical characterisation of an FDM 3D printing process

3D printing (3DP) of pharmaceutical formulations via commercially available FDM pinters has gained interested in recent years, enabling personalisation of medicines. It also facilitates advanced control of the microstructure of the tablet core, permitting fine tuning of product release characteristics with a single formulation. In addition, the technology also offers a platform for Dose escalation studies employing a single formulation and single manufacturing step. The objective of this study was to perform a mechanical characterisation of the extrusion of pharmaceutically relevant feedstock material during an FDM process

Printability of pharmaceutical Fused Deposition Modeling (FDM) feedstock material : mechanical characterisation of FDM filaments and the FDM 3D printing process

Purpose -- 3D printing (3DP) of pharmaceutical formulations via commercially available FDM printers facilitates advanced control of the microstructure of the tablet core and therefore drug release properties. For this 3DP process an intermediate feedstock material is manufactured and used in the FDM process. However, mechanical and rheological properties of pharmaceutically approved polymers are often not suitable for this process. In order to identify suitable filaments for the FDM process, the objective of this study was to perform a mechanical and rheological characterisation of the feedstock material during an FDM process. Conclusions -- Mechanical properties of an FDM process for commercial and in-house prepared pharmaceutically relevant feed stock material were investigated and have shown the material dependant impact of print geometries and print speed on the FDM process; informing future development of pharmaceutically relevant feedstock material