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Scale-Up and GMP Plant Design Pharmaceutical Particle Engineering by the SEDS Process
By Srinivas Palakodaty, Head of Process Engineering, Stephen Walker, Development Director, George Townend, Engineering and Facilities Manager, Peter York, Chief Scientist, and Gwyn Humphreys, Managing Director, of Bradford Particle Design
With a growing demand for engineered particles in drug delivery to improve therapeutic performance, traditional particle formation methods are increasingly being found to be limited in meeting stringent requirements. New approaches are required. However, whilst novel technologies can seem extremely promising during laboratory and early developmental phases, many fail on scale-up and on meeting the tighter controls imposed by the pharmaceutical industry and regulatory authorities. Further challenges to establishing new technologies commercially are their adaptability when complying with current Good Manufacturing Practice (cGMP).
Supercritical fluid technology, and especially the solution enhanced dispersion by supercritical fluids (SEDS) (1) process, has shown great promise in applications such as preparing particulate pharmaceuticals with defined physicochemical properties. This article discusses the various scale-up issues and GMP requirements that have been addressed by the SEDS process.
THE NEED FOR PARTICLE ENGINEERING IN DRUG DELIVERY

For many new drugs, the need for improved and efficient drug delivery systems has become apparent, especially when administered in a particulate form. For example, in respiratory drug delivery, effective deep lung deposition is achieved with particles of one to five microns in size. Current size reduction methods, such as fluid energy milling (or micronising), are capable of achieving the target size range, but the high energy required for such processes often damages the crystal surface, leading to highly charged and cohesive particles which results in the chemical and physical instability of the drug. In addition, the particle properties can vary from batch to batch causing problems in downstream processing and product formulation.

At the same time, stringent controls exist for the chemical properties of particles, with emphasis on purity, polymorphic form, and residual solvent levels in the particulate products. Conventional solvent crystallisation is laborious, sometimes taking extended periods to form the desired polymorphs or repeated crystallisation steps in order to achieve targeted purity levels. Moreover, crystallisation is often difficult to control and scale-up, and such particle formation is usually associated with long drying times and additional downstream processing steps. Alternative particle formation techniques, such as spray drying, are thermally intensive, thus limiting their use for many new thermolabile therapeutic agents such as proteins and peptides.
SUPERCRITICAL FLUID METHODS FOR PHARMACEUTICAL PARTICLE DESIGN

In recent years, interest in supercritical fluid (SCF) methods for engineering particulates with well-defined physicochemical properties has grown. The SEDS process, shown schematically in Figure 1, utilises the SCF as a dispersing antisolvent and as a medium for extracting the solvent for efficiently

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precipitating a solute from organic or aqueous solution. In this process, the drug is dissolved in an organic solvent and the solution is co-introduced with the SCF through the annuli of a two-fluid coaxial nozzle (1). The two streams are thoroughly mixed in the nozzle to ensure efficient dispersion and mixing. Dry particles, formed after solvent extraction by the SCF, are collected in a vessel kept at constant temperature and pressure. Unlike other approaches using SCFs, the SEDS process is efficient in preparing particles in the size range 0.5 to 30 m with a narrow size distribution, with controlled solid state properties and with low residual solvent content. Another distinguishing feature is the ability to prepare polymorphs including metastable and stable forms (2). Processing water soluble compounds, especially biologicals, has been a major problem for SCF methods because of the immiscibility of water and the most commonly used SCF, carbon dioxide (CO2). However, a modified SEDS process has successfully overcome this issue. In the modified process, a second solvent which is completely miscible with both water and supercritical CO 2 typically ethanol, methanol or acetone is used, and the three-fluid streams are introduced separately through the annuli of a three-fluid coaxial nozzle (3), as shown in Figure 1. Another way of introducing the streams is by mixing the organic feed and supercritical CO2 to obtain a homogeneous phase and then contacting it with an aqueous stream in a twofluid nozzle (4). The SCF extracts the water and solvent and the dry particles are then collected and retained in the vessel. Typical product recoveries in the single step SEDS process are greater than 95 per cent, offering significantly higher yields than the conventional multistage sequence of crystallisation, harvesting, drying, sieving and milling in order to obtain particles of required properties. Table 1 lists the typical applications of the SEDS process for the pharmaceutical industry, demonstrating the breadth of this platform technology. Figure 2 (overleaf) serves as an example illustrating the degree of control the SEDS process has in achieving wellfaceted crystals of nicotinic acid in the sub 5 m size range. The process conditions of temperature, pressure and flow rates of the individual streams are optimised based on several parameters including drug solubility in pure and solvent modified

Figure 1: Schematic Drawing of the SEDS Process Showing the Nozzle Arrangement

Aqueous Solution Organic Solvent Pump Cooler Pump Nozzle Atomisation Vessel Filter Oven Back Pressure Regulator CO2 Aqueous Solution Organic Solvent Two Fluid Nozzle CO2 (+organic solvent) Organic/Aqueous Solution

CO2 Pump Heat Exchanger Pulse Dampener

CO2 Cylinder

Back Pressure Regulator

Cyclone Seperator

Solvent

Three Fluid Nozzle

SCF, and the solvent-SCF phase equilibrium data. The scale-up strategy is directed by, and builds on research findings in fluid dynamics and phase equilibria.
SEDS AS A GMP MANUFACTURING PROCESS

As with any new technology being introduced into the pharmaceutical industry, the commercial viability of the process depends on the degree of process robustness and reliability, and its ability to comply with current GMP regulations. GMP compliance necessitates properly designed, installed and commissioned equipment. Validation is vital for both the equipment and the process. An attractive factor for SEDS in these respects is the totally enclosed particle Table 1: Typical Applications of the SEDS Process for Pharmaceuticals
Application
Sized drug particles Sized drug particles Excipients Biologicals (proteins, peptides etc) Polymorphism Residual solvent level Composite particles (for example, drug-polymer matrix) Coating Solid state chemistry Modified drug release Crystalline/amorphous phases 9 9 New polymorphs, Pure polymorphs (metastable, stable) Below regulatory limits Enhanced dissolution, modified release 7 8 2,5

Objective
1-5 m Less than 1 m Size, morphology 1-5 m

Reference
2,5 9 4 6

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formation environment, eliminating the risk of contamination during processing. The SEDS process has been scaled up to a 10 litre particle formation vessel with a liquid CO2 pump capable of delivering 50 kg per hour. The plant has cyclone separators to recover the process solvent allowing the process CO2 to be recycled. The high pressure equipment is made of 316L grade stainless steel, and meeting the regulatory requirement of a surface roughness of less than 0.5 m does not pose a challenge for the pressure vessels and tubes. Nevertheless, the high pressure valves had to be specially designed with minimal dead volume to ease cleaning and to suit the needs of the pharmaceutical industry. The seals are made of PTFE, which is classed as a generally regarded as safe (GRAS) material. In addition, as the SEDS plant is a combination of several individual components pressure vessels, high pressure valves, high pressure tubing and so on it is extremely important to work closely with equipment manufacturers during the design stage to co-ordinate and collate all the necessary documentation for validating the plant. For GMP and operational compliance, an important parallel issue is that of the facility housing the process equipment. A high pressure process such as SEDS involves various utilities including hot and cold fluids, de-ionised water and compressed air. Having all this ancillary equipment in a controlled air environment can Figure 2: SEM of Nicotinic Acid Prepared by the SEDS Process

be very expensive and impractical. This issue has been addressed by separating the atomisation vessel from the main process skid and all the ancillaries. Only the atomisation vessel holding the particulate product and the tanks holding the drug solution are housed in a controlled ISO Class 7 area (see Figure 3). The process skid and the ancillaries are housed in an unclassified area (see Figure 4). For the manufacture of large quantities of product, the SEDS process is, at present, a quasicontinuous operation, and in order to recover individual batches, the process is stopped and the vessel depressurised. The product is collected in a 0.8 m pore size PTFE filter bag within the pressure vessel. After opening the vessel, the bag is capped and taken into a laminar flow powder handling booth for packaging. This is an attractive procedure for handling fine particles, with clear benefits over conventional milling operations. The heating, ventilation and air conditioning (HVAC) system is computer controlled with logs of pressure, temperature and humidity for use in batch documentation records. The operation of the SEDS process is controlled by macroscopic variables such as temperature, pressure and the flow rate of the relevant CO2 and solution streams. The process is completely computer controlled, including all the necessary safety alarms for handling high pressure systems. The control software has two levels of hierarchy user and supervisory levels. At the user level, the software runs a set protocol for manufacturing a batch of drug material. It does not allow the process variables to be changed and has additional features including process monitoring and recording the operating parameters. This also forms a key feature in batch documentation. Access to the process area for people and materials is available through air locks to maintain the ISO class 7 conditions within the process area. In addition, the facility has important safety features including high CO2 and low oxygen detectors. As with any high pressure equipment, particularly when coupled with the manufacture of particulates, safety is a major concern. The SEDS manufacturing process has an integrated 430 litre capacity stainless steel surge tank capable of holding the contents of the entire system at a pressure of 10 bar. This is a very important safety feature and can be used to retain

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Figure 3: View of the SEDS Atomisation Vessel in an ISO Class 7 Area (Plant Constructed by Separex Chimie Fine, France)

Figure 4: View of the SEDS Plant with Various Ancillaries Housed in an Unclassified Area (Plant Constructed by Separex Chimie Fine, France)

all the active material in case the vessel has to be depressurised in an uncontrolled manner. Contamination during processing and between batches of different products is a major issue in processing pharmaceuticals. As the SEDS process for particle formation is completely enclosed, there is no scope for external contamination during processing. Equipment cleaning is critically important to avoid the cross contamination of different materials when the equipment is used for processing multiple products. For the current SEDS manufacturing plant, validated cleaning procedures have been developed. Future developments of the SEDS plant are currently focused on continuous product recovery to decrease shutdown time and full clean in place (CIP) facility.
THE FUTURE

(2)

Beach S, Hanna M, Latham D, Sidgwick C, York P, Control of the Physical Form of Salmeterol Xinafoate, Org Proc Res Devel: 3, pp370-376, 1999

(3)

Hanna M, York P, Method and Apparatus for the Formulation of Particles, European Patent 0767702B1, 1998

(4)

Palakodaty S, Pritchard J, York P, Supercritical Fluid Processing of Materials from Aqueous Solutions: The Application of SEDS to Lactose as a Model Substance, Pharm Res: 15, pp1835-1843, 1998

(5)

Hanna M, York P, Particle Engineering by Supercritical Fluid Technologies for Powder Inhalation Drug Delivery, In Proceedings of

Respiratory Drug Delivery V, Pheonix, USA,

pp231-239, ISBN 1-57491-018-3, 1996 (6) Ashraf W, Hoare M, Hollowood ME, Humphreys GO, Sarup L, Sloan R, Tservistas M, York P, Controlled Particle Formation of Biological Material Using Supercritical Fluids, Proceedings

With an ever-increasing demand for particles of pharmaceutical materials with defined physical and chemical characteristics, the benefits offered by SCF processing such as the SEDS process are increasingly being recognised. In view of the fact that this single stage process is readily scaleable and is able to comply with the regulations and norms of GMP, an attractive solution is available to address many of the issues in engineering pharmaceutical materials and particle design. N
References (1) Hanna M, York P, Method and Apparatus for the Formation of Particles, European Patent 0706421B1, 1998

of the 6th Meeting on Supercritical Fluids, (ISBN

2-905-267-30-5), Nottingham, UK, pp169-174, 1999 (7) Gilbert D, Palakodaty S, Sloan R, York P, Particle Engineering for Pharmaceutical Applications, Proc.

5th ISSF Meeting, Atlanta, USA, pp21-22, 2000

(8) Wilkins SA, York P, Roberts RJ, Rowe RC, McConvey IF, The Formation of Indomethacin: Polymer Coprecipitates by the Solution Enhanced Dispersion by Supercritical Fluids (SEDS) Process, J. Pharm. Pharmacol: 51, 291, 1999 (9) Unpublished bpd data

Author can be contacted at info@bpd.co.uk Reprinted from European Pharmaceutical Contractor August 2000 issue. Copyright: Samedan Ltd. 2002