- Email: [email protected]
Small is beautiful
editorial
PSTT Vol. 3, No. 6 June 2000
Small is beautiful ‘The solution to an age old problem is now at hand.’ Raymond C. Rowe Research Associate AstraZeneca Alderly Park, Macclesfield Cheshire UK SK10 2NA tel: +44 1625 513112 fax: +44 1625 512381 e-mail: [email protected]
▼ In a recent article1, Ole Bjerrun, Chair of the European Federation for Pharmaceutical Sciences Committee on Industrial Relations gave details of a proposal to bring pharmaceutical sciences in focus for the European Union’s 6th Framework Programme 2003–2007. Under the title New Safe Medicines Faster, the objectives outlined are ‘firstly, to develop new technologies capable of more effective selection of potential drug candidates for innovative medicines while accommodating safety demands; secondly, to use such technologies to speed up pharmaceutical development and eliminate foreseeable bottlenecks created by the many drug candidates now generated in the discovery phase; and thirdly, to cultivate a pan-European interdisciplinary network on science and training that bridges the gap between pharmaceutical industry and academia.’
Miniaturization in the pharmaceutics These are indeed laudable objectives and ones that I wholeheartedly support, as I am sure do most PSTT readers. Among the new technologies highlighted by Bjerrun was one of specific interest to me personally – that of miniaturization in pharmaceutics. The problem of formulating and producing an oral dosage form, especially one that has a modified release profile, using small quantities of an expensive and scarce new drug candidate is a perennial one. Indeed, in my own experience of 30 years in the industry, I have had two occasions to regret the non-availability of equipment to do the job. On both occasions, I was asked to produce a 14C-labelled controlled release oral dosage form for human studies using a specification equivalent to that of the non-labelled formulation but using very limited quantities of drug.
Equipment design Fortunately, three years ago, I was asked to initiate a project in the field of miniaturization. Working with a small team of engineering
colleagues, several pieces of equipment were designed and prototyped to cover the processes of mixing/granulation, extrusion/ spheronization, tabletting and film coating. All the equipment was designed to specific criteria in terms of size and performance (safety being paramount in all cases). Size was defined in terms of portability, ease of cleaning and operation with single-phase electrics, thus enabling the equipment to be moved when required or operated in different containment regimes. Performance was defined in terms of ease of operation, reproducibility and instrumentation with a proven/demonstrable scale-up path. At the outset, it was obvious that any design based on geometric and kinematic similarity used by engineers for scaling-up was out of the question and that lateral thinking is what was required. Finally, after several iterations, prototypes were manufactured at various degrees of sophistication but all using accurate and quality instrumentation to enable product properties to be accurately measured and scaled. Mixing and granulation have been centred around a mixer torque rheometer (Caleva Process Solutions, Sturminster Newton, UK), as extensive research has demonstrated that the output from this rheometer is a measure of the wet mass consistency and directly related to the dry granule properties of size, friability and flow2, as well as being a property that can be used for scaling-up in both geometrically similar3,4 and nonsimilar5 mixers. A half-sized bowl has been designed enabling the mixing of 7–10 g of powder/wet mass. Miniaturization of extrusion has been centred around a ram extruder with a 25 mm diameter barrel, as extensive research has demonstrated that this is related to the ease of extrusion of the formulation suitable for spheronization6. Meanwhile, miniaturization of spheronization has been centred around units with bowl diameters half that of the current small-scale spheronizers7. The ram extruder has been designed to operate in a bench top, instrumented, computer-controlled hydraulic press that is capable of crosshead speeds of up to 300 mm s21. Incidentally, this press has also been designed to compact tablets using standard punches and dies and can be operated either under force or displacement control. Experiments have shown that the accuracy of the press is better than that currently achieved by large compaction simulators and yet it is small enough to fit in a standard fume cupboard. In many ways, the design of a single tablet coating machine was relatively easy as one based on a vibrating bed has already been described in the literature8. A modified design with full instrumentation has been found to be capable of coating batches of up to 20 tablets (depending on the diameter) or batches of pellets up to 15 g using both aqueous- or organic solvent-based formulations with a high degree of accuracy and reproducibility.
1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00265-0
187
editorial
PSTT Vol. 3, No. 6 June 2000
All prototypes have been extensively evaluated and shown to meet both operational and performance specifications, and they are currently being commercialized by an equipment manufacturer (Caleva Process Solutions). Future ideas being considered are the linking of each piece of equipment to a central computer enabling the introduction of a central management system which, in addition to producing relevant documentation, could also include decision support systems for the recommendation of formulations and process conditions9. It is now possible to formulate and produce complex formulations of oral dosage forms that are scaleable or equivalent to those produced on a large scale, but using limited quantities of a drug candidate. The solution to an age-old problem is now at hand. I wish it had been around 30 years ago!
02 Faure, A. et al. (1999) Process control in a high shear mixer granulator using wet mass consistency: the effect of formulation variables. J. Pharm. Sci. 88, 191–195 03 Landin, M. et al. (1996) Scale-up of a pharmaceutical granulation in a fixed bowl mixer granulator. Int. J. Pharm. Sci. 133, 127–131 04 Faure, A. et al. (1999) Applicability of a scale-up methodology for wet granulation process in a Colette Gral high shear mixer granulator. Eur. J. Pharm. Sci. 8, 85–93 05 Faure, A. et al. (1998) Importance of wet mass consistency in the control of wet granulation by mechanical agitation – a demonstration. J. Pharm. Pharmacol. 50, 1431–1432 06 Fielden, K.E. et al. (1992) The influence of lactose particle size on the spheronisation of extrudate processed by a ram extruder. Int. J. Pharm. 81, 205–224 07 Rowe, R.C. and Iles, C. (1995) Spheronisation systems downscaled for
These are the personal views of the author and do not necessarily represent those of AstraZeneca.
08 Alkan, M.H. et al. (1998) Small-scale film coating of tablets, pellets and
References
09 Rowe, R.C. and Roberts, R.J. (1998) Artificial intelligence in
research. Manuf. Chem. 66(11), 35–37 granules. Pharm.Technol. 12(6), 98–104
01 Bjerrun, O. (1999) The pharmaceutical sciences and EU’s RTD framework programmes. Eur. J. Pharm. Sci. 9, v–vii
pharmaceutical product formulation: knowledge based and expert systems. Pharm. Sci.Technol.Today 1, 153–159
In the July issue of Pharmaceutical Science & Technology Today… Update – latest news and views Formulation and technology aspects of controlled drug delivery in animals A. Rothen-Weinhold, M. Dahn and R. Gurny Latest advances in the development of dry powder inhalers I. Ashurst, A. Malton, D. Prime and B. Sumby The use of PAMAM dendrimers in the efficient transfer of genetic material into cells J.D. Eichman, A.U. Bielinska, J.F. Kukowska-Latallo and J.R. Baker, Jnr Monitor – process technology, drug delivery, analytical methodologies, legislative issues, patents, invited profile Products
188
PSTT Vol. 3, No. 6 June 2000
Small is beautiful ‘The solution to an age old problem is now at hand.’ Raymond C. Rowe Research Associate AstraZeneca Alderly Park, Macclesfield Cheshire UK SK10 2NA tel: +44 1625 513112 fax: +44 1625 512381 e-mail: [email protected]
▼ In a recent article1, Ole Bjerrun, Chair of the European Federation for Pharmaceutical Sciences Committee on Industrial Relations gave details of a proposal to bring pharmaceutical sciences in focus for the European Union’s 6th Framework Programme 2003–2007. Under the title New Safe Medicines Faster, the objectives outlined are ‘firstly, to develop new technologies capable of more effective selection of potential drug candidates for innovative medicines while accommodating safety demands; secondly, to use such technologies to speed up pharmaceutical development and eliminate foreseeable bottlenecks created by the many drug candidates now generated in the discovery phase; and thirdly, to cultivate a pan-European interdisciplinary network on science and training that bridges the gap between pharmaceutical industry and academia.’
Miniaturization in the pharmaceutics These are indeed laudable objectives and ones that I wholeheartedly support, as I am sure do most PSTT readers. Among the new technologies highlighted by Bjerrun was one of specific interest to me personally – that of miniaturization in pharmaceutics. The problem of formulating and producing an oral dosage form, especially one that has a modified release profile, using small quantities of an expensive and scarce new drug candidate is a perennial one. Indeed, in my own experience of 30 years in the industry, I have had two occasions to regret the non-availability of equipment to do the job. On both occasions, I was asked to produce a 14C-labelled controlled release oral dosage form for human studies using a specification equivalent to that of the non-labelled formulation but using very limited quantities of drug.
Equipment design Fortunately, three years ago, I was asked to initiate a project in the field of miniaturization. Working with a small team of engineering
colleagues, several pieces of equipment were designed and prototyped to cover the processes of mixing/granulation, extrusion/ spheronization, tabletting and film coating. All the equipment was designed to specific criteria in terms of size and performance (safety being paramount in all cases). Size was defined in terms of portability, ease of cleaning and operation with single-phase electrics, thus enabling the equipment to be moved when required or operated in different containment regimes. Performance was defined in terms of ease of operation, reproducibility and instrumentation with a proven/demonstrable scale-up path. At the outset, it was obvious that any design based on geometric and kinematic similarity used by engineers for scaling-up was out of the question and that lateral thinking is what was required. Finally, after several iterations, prototypes were manufactured at various degrees of sophistication but all using accurate and quality instrumentation to enable product properties to be accurately measured and scaled. Mixing and granulation have been centred around a mixer torque rheometer (Caleva Process Solutions, Sturminster Newton, UK), as extensive research has demonstrated that the output from this rheometer is a measure of the wet mass consistency and directly related to the dry granule properties of size, friability and flow2, as well as being a property that can be used for scaling-up in both geometrically similar3,4 and nonsimilar5 mixers. A half-sized bowl has been designed enabling the mixing of 7–10 g of powder/wet mass. Miniaturization of extrusion has been centred around a ram extruder with a 25 mm diameter barrel, as extensive research has demonstrated that this is related to the ease of extrusion of the formulation suitable for spheronization6. Meanwhile, miniaturization of spheronization has been centred around units with bowl diameters half that of the current small-scale spheronizers7. The ram extruder has been designed to operate in a bench top, instrumented, computer-controlled hydraulic press that is capable of crosshead speeds of up to 300 mm s21. Incidentally, this press has also been designed to compact tablets using standard punches and dies and can be operated either under force or displacement control. Experiments have shown that the accuracy of the press is better than that currently achieved by large compaction simulators and yet it is small enough to fit in a standard fume cupboard. In many ways, the design of a single tablet coating machine was relatively easy as one based on a vibrating bed has already been described in the literature8. A modified design with full instrumentation has been found to be capable of coating batches of up to 20 tablets (depending on the diameter) or batches of pellets up to 15 g using both aqueous- or organic solvent-based formulations with a high degree of accuracy and reproducibility.
1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00265-0
187
editorial
PSTT Vol. 3, No. 6 June 2000
All prototypes have been extensively evaluated and shown to meet both operational and performance specifications, and they are currently being commercialized by an equipment manufacturer (Caleva Process Solutions). Future ideas being considered are the linking of each piece of equipment to a central computer enabling the introduction of a central management system which, in addition to producing relevant documentation, could also include decision support systems for the recommendation of formulations and process conditions9. It is now possible to formulate and produce complex formulations of oral dosage forms that are scaleable or equivalent to those produced on a large scale, but using limited quantities of a drug candidate. The solution to an age-old problem is now at hand. I wish it had been around 30 years ago!
02 Faure, A. et al. (1999) Process control in a high shear mixer granulator using wet mass consistency: the effect of formulation variables. J. Pharm. Sci. 88, 191–195 03 Landin, M. et al. (1996) Scale-up of a pharmaceutical granulation in a fixed bowl mixer granulator. Int. J. Pharm. Sci. 133, 127–131 04 Faure, A. et al. (1999) Applicability of a scale-up methodology for wet granulation process in a Colette Gral high shear mixer granulator. Eur. J. Pharm. Sci. 8, 85–93 05 Faure, A. et al. (1998) Importance of wet mass consistency in the control of wet granulation by mechanical agitation – a demonstration. J. Pharm. Pharmacol. 50, 1431–1432 06 Fielden, K.E. et al. (1992) The influence of lactose particle size on the spheronisation of extrudate processed by a ram extruder. Int. J. Pharm. 81, 205–224 07 Rowe, R.C. and Iles, C. (1995) Spheronisation systems downscaled for
These are the personal views of the author and do not necessarily represent those of AstraZeneca.
08 Alkan, M.H. et al. (1998) Small-scale film coating of tablets, pellets and
References
09 Rowe, R.C. and Roberts, R.J. (1998) Artificial intelligence in
research. Manuf. Chem. 66(11), 35–37 granules. Pharm.Technol. 12(6), 98–104
01 Bjerrun, O. (1999) The pharmaceutical sciences and EU’s RTD framework programmes. Eur. J. Pharm. Sci. 9, v–vii
pharmaceutical product formulation: knowledge based and expert systems. Pharm. Sci.Technol.Today 1, 153–159
In the July issue of Pharmaceutical Science & Technology Today… Update – latest news and views Formulation and technology aspects of controlled drug delivery in animals A. Rothen-Weinhold, M. Dahn and R. Gurny Latest advances in the development of dry powder inhalers I. Ashurst, A. Malton, D. Prime and B. Sumby The use of PAMAM dendrimers in the efficient transfer of genetic material into cells J.D. Eichman, A.U. Bielinska, J.F. Kukowska-Latallo and J.R. Baker, Jnr Monitor – process technology, drug delivery, analytical methodologies, legislative issues, patents, invited profile Products
188