Robert Price

Delivering medicines to the human body has always met with technological and physical challenges. Recent advances in powder and material processing and characterization methods allow formulators and engineers to design increasingly elaborate drug delivery systems. However, many obstacles need to be overcome to successfully develop and introduce these products. 

The constant requirement for the targeted delivery of therapeutically active agents has been the key driver in particle engineering and processing within the pharmaceutical sector. These increasingly complex agents are posing greater challenges to formulators because of their solubility, stability and other physicochemical properties. Consequently, development projects tend to be designed based on an evaluation of current practices and, most importantly, the perceived challenges of introducing potential new particle processing technologies and the possible implications of the regulatory developments requirements; for example, The Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance — process analytical technology (PAT) and The International Conference on Harmonisation of Technical Requirements or Registration of Pharmaceuticals for Human Use Quality 8 (ICH Q8).

The common strategy for producing a pharmaceutical solid dosage form is based on a growth of scale; that is, the active pharmaceutical ingredient (API) molecule is engineered to a crystal form, which is then processed into particles and finally 'formulated' into the dosage form. The particle processing typically uses a destructive, energetic 'top-down' technique to reduce the API to the required particle size range for a particular dosage form. 

These techniques, such as fluid air-jet milling, were introduced in the late 1930s and early 1940s and have been applied in a wide variety of industrial applications, including processing pigments and pesticides. Previously, only limited technological advances have been achieved for these processing techniques; for example, changes to the geometries of the milling chambers and product-feed units, and developments in particle filtration have led to an increase in productivity, product yield and specificity. This milling approach to particle engineering is energy-intensive, involves extravagant use of resources and time and, more critically, can adversely affect a whole range of highly important material physicochemical properties, which may have significant effects on product stability and clinical performance. 

While there is an ever-increasing need to address these issues, the industry generally remains reluctant to embrace new particle engineering technologies, and their development for scale-up processing of APIs and excipients. The perceived resistance may relate to the risk-adverse culture that has developed within the highly regulated pharmaceutical manufacturing sector and, moreover, within the product development groups. This is in complete contrast with drug discovery where innovation is encouraged. The validation-based approach to pharmaceutical processing and manufacturing has not only stifled innovation, but also the motivation to improve product development and manufacturing efficiency. Other factors that have limited the introduction of new particle engineering technologies include the costs of implementation, support and the required equipment.

Thus, novel particle engineering technologies have remained limited to extending product life cycles, and where conventional particle technologies are unable to produce the physicochemical properties and/or stability required for a particular dosage form. 

The welcome introduction of regulatory guidance such as PAT, ICH Q8 and the proposed ICH Q9 will manoeuvre the industry towards a more scientific- and engineering-based relationship with their materials and processes involved in pharmaceutical product development and manufacturing and, importantly, their effect on product quality. Their implementation may not only overcome some of the constraints the industry has been subjected to over the years, but also provide the impetus and opportunity for the continuous development of product quality by the design and development of material processing technologies. 

One of the major concerns with introducing PAT, however, is that the bias towards process engineering may not ultimately lead to complete control of product quality. While the focus towards improved understanding of the process parameters of unit operations (e.g., temperature, spectroscopic analysis and moisture content) will lead to the development of high-tech process control technologies, it is inevitable that, for a significant number of applications, the traditional methods for preparing, and the specific functionality of APIs and excipients will become the critical component of product quality and performance. 

Thus, while all the critical sources of variability may be identified using a guidance-led approach, the variables may be on a scale that cannot be controlled by current practices in particle engineering, processing and characterization. The development and shift away from understanding processing parameters of unit operations towards a more tailored approach regarding specific functionality and product properties using particle engineering and formulation technologies, has already occurred within the chemical engineering sector. 

The industry must, therefore, make a concerted effort to understand product engineering through a greater realization and control of product properties and process attributes. Importantly, as ICH Q8 states that "quality cannot be tested into products, i.e., quality should be built in by design", it is vital that any relationships between processing operations, product components and product quality should be understood. This research may provide pharmaceutical companies with a greater competitive edge and protect future drug products from generic competition as they may be unable to match product performance and therapeutic efficacy. 

It is important to state that while novel particle processing technologies have had limited success, alternative approaches have been used to enable effective drug delivery to the body. For example, polymorphic engineering of APIs can be successfully used to impart a specific drug property offering improvements in, for example, solubility and stability. Additionally, excipient manufacturers have produced a range of products that can modify the formulation, processing and delivery of APIs through elaborate excipient material and particle engineering. 

Control release excipients can target specific parts of the gastrointestinal tract (GIT)

and materials, such as cyclodextrins, can be used to address solubility issues. However, even though these increasingly elaborate products have created and continue to introduce tremendous possibilities for drug delivery, they achieve this through secondary particle engineering; that is, the API is postprocessed. The challenge is to produce APIs and technologies where the properties are simply engineered to a specific use rather than rely on secondary materials for formulation, processing and efficacy. 

Successful implementation of such an approach requires the introduction of a series of technological advances in particle engineering and material processing. Nektar (San Carlos, CA, USA) developed a dry powder insulin product called Exubera by processing insulin with selected excipients for drug delivery via the lungs. It has successfully developed and scaled-up the processing of macromolecules using its proprietary high glass transition (T

) glass stabilization technology, which is based on controlling and manipulating the properties of a mixture of excipients.

  This spray drying-based technology has overcome the traditional stability problems (e.g., aggregation, deamidation and oxidation) typically associated with proteins and peptides under storage at room temperature through using glassy sugars to protect the fragile macromolecules from denaturation. 

The success of this technological advancement has not only been in the particle engineering and its scale-up, but also in powder handling, where accurate and reproducible blister filling of 1–5 mg has been achieved under humidity protection.

  The triumph in overcoming the numerous technical and scientific hurdles may provide Nektar and its partners with a long-term competitive advantage in the dry powder inhaler delivery market of insulin and other macromolecules, possibly well beyond the patent lifetime of the developed technologies. 

Conversely, the disposal of Nektar's supercritical fluid (SCF) particle engineering technology and the closure of its UK operation has highlighted the significant issues relating to the successful scale-up of novel particle engineering systems even when they are in their advanced stage of development and commercialization. It was deemed that the SCF platform technology would not produce products that fitted with their future business strategy. 

Another novel approach is the particle engineering of biomolecules using protein-coated microcrystals (PCMCs). The formulation and stabilization technology of proteins, nucleic acids and vaccines by the coprecipitation of a water-soluble carrier, such as amino acid or carbohydrate, with a dehydrated biological macromolecule, makes them highly suitable for delivering biomolecules by a number of routes, including pulmonary and parenteral administration.

  XtalBio's PCMC technology (Glasgow, UK) and Boehringer Ingelheim has highlighted the potential of this new formulation and delivery systems for biological entities. 

One of the ongoing challenges for the formulation and preclinical evaluation of new chemical entities (NCEs) is that a significant number of lead candidates from drug discovery and high-throughput screening exhibit poor solubility. With the increasingly lipohphilic nature of the candidate drugs, solubility and dissolution rates have become the limiting factors that affect bioavailability of oral and parenteral formulations. While advanced technologies for enhancing delivery of poorly soluble drugs have included using polymorphic engineering, solid-dispersions, microemulsions, self-emulsifying systems, complexation and liposomes, a truly particle engineering-based solution remains particularly desirable to the pharmaceutical industry. The key advantages for developing such systems are the tailoring of the drug to the delivery requirements; the use of conventional processing and formulation; and that any safety issues regarding intravenous preparations, and the use of cosolvents and excipients may be overcome. 

Another approach to enhance drug dissolution rates for drug targeting purposes is the processing of nanoscale drug particulates; the nanoscale being defined as 100 nm down to the size of atoms (~0.2 nm). However, while 'true' nanoparticles may not have yet been incorporated into pharmaceutical dosage forms, submicron-sized particles have been successfully used to improve the rate of dissolution and bioavailability of poorly soluble drugs. Elan's NanoCrystal technology (Athlone, Ireland) has been applied to optimize the performance of established drugs and as an enabling technology for NCEs.

  Here, drug particles less than 1 μm are produced by a wet-milling technique. The low-energy ball-milling process takes a relatively long time (a minimum of 4-5 days) to produce a suitable aqueous colloidal dispersion of the ultrafine particles containing an appropriate surfactant to stabilize the particles against agglomeration and degradation. 

More recent research developments in engineering pharmaceutical nanosized drug particles have been based on a 'bottom-up' approach, either by a droplet formation and evaporation approach, a solvent precipitation method or a combination. 

A novel approach has been developed to produce dry drug particles by controlled droplet evaporation of nanosized droplets of a drug solution in an aerosol flow reactor.

  The continuous, single-step operation produces nanosized particles with narrow particle size distributions. The main issue to overcome with this approach is the scalability of the flow reactor for pilot and industrial commercialization, and the active control of the solid-state properties; for example, crystallinity of the particles during solvent evaporation. 

Spray freeze-drying technologies have also been developed for creating nanostructured drug particles. The drug, which is dissolved in a water-miscible solvent together with a crystal growth inhibitor, is actively dispersed into a freezing medium, such as liquid nitrogen, followed by solvent removal by lyophilization.

  The resultant particles are agglomerated and highly porous with a yield of almost 100%. The process is expensive because it requires cryogenic technology, and the control of precipitation depends on the rate of solvent removal with the drying process. 

A recent modification of the conventional supercritical antisolvent approach has led to an enhanced mass transfer between the solvent and antisolvent, and the reduction of the particle size to submicron size range by the application of an ultrasonic field. The cogeneration of smaller droplets and increased turbulence, and mixing solvent droplets within the supercritical CO

 phase is generated by targeting a jet of the solution at a well-defined angle on to an ultrasonic horn oscillating at 20 Hz.

  The supercritical antisolvent with enhanced mass transfer (SAS–EM) is, however, limited by the scalability of the supercritical rig, the relatively slow solution transfer rate through the 75 μm capillary and the broad product particle size distributions. 

A novel precipitation method for controlling the nucleation and crystallization of nanosized drug particles involves using high-gravity micromixing.

  High-gravity is formed using a rotating packed bed (15–50 Hz), which intensifies the mixing between multiphase systems inducing nucleation and crystal growth. The reactive precipitation mode has been successfully used in mineral processing at a commercial production scale (10000 tonnes/annum) and can control the particle size distribution by altering the rotating speed, solution concentrations or flow rates. 

A unique particle engineering technology incorporating a combination of droplet evaporation and antisolvent crystallization by a sonication process known as solution atomization and crystallization by sonication (SAX [Prosonix; Oxford, UK]), which

has been developed to produce nanoparticles within a well-defined particle size range while manipulating the nucleation and crystal growth process within the supersaturated droplets.

The SAX technology has shown significant benefits in the modification and control of the macroscopic morphology, and surface topography of the crystalline nanoparticles, which, because of the dominant nature of the surface forces, play a critical role in the characteristic properties of nanoparticles. 

With the obvious potential of nanoparticles in pharmaceutical delivery systems it can be anticipated that particle engineering technology needs to undergo considerable growth and advances over the coming years. Additionally, there is a further requirement for the industry to develop new high-tech scalable processes that are capable of handling these materials, and ensuring that the inability to formulate and manufacture these products is not the bottleneck for their application in pharmaceutical products.

Considering that the current level of development of pharmaceutical particle technologies is relatively limited, and the understanding of the relationships between such materials and processes in the development and manufacturing of pharmaceutical products is at an early stage, there remains an onerous path for the successful development and implementation of particle-based technologies in the pharmaceutical industry.? 

is a reader at the Department of Pharmacology and Pharmacology, University of Bath (UK), where he leads the pharmaceutical surface science research group. 

 is a visiting scientist, also at the Pharmaceutical Surface Science Group, University of Bath (UK).			

1. Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, Food and Drug Administration (September 2004). 

3. J.S. Patton, L. Foster and R.M. Platz, "Methods and compositions for pulmonary delivery of insulin," US 5,997,848 (1997). 

5. B.D. Moore, M.C. Parker and P.J. Halling, "Rapid dehydration of proteins," WO0069887 (2000). 

., "Process for preparing therapeutic compositions containing nanoparticles," US 5,510,118 (1996). 

., "Method for the preparation of nanoparticles," US2004/0091542 (2004). 

9. R.B. Gupta and P. Chattopadhyay, "Method of forming nanoparticles and microparticles of controllable size using supercritical fluids and ultrasound," US60/206,644 (2000). 

Articles

One of the major concerns with introducing PAT, however, is that the bias towards process engineering may not ultimately lead to complete control of product quality.

Developments in particle engineering processes for pharmaceutical drug delivery systems

Dry powder inhaler (DPI) products typically consist of a device containing a blend of micron-sized drug particles and larger, so-called 'inert' carrier particles. Upon aerosolization, the drug is liberated from the carrier using the inspiration force of the patient to penetrate the lung. The carrier, typically alpha-lactose monohydrate, is used as a diluent and flow aid, improving content uniformity and stability, and to facilitate reproducibility in emitted dose. However, even though there are many marketed DPIs, it is clear that the successful manufacturing of a DPI product still poses many technological, regulatory and scientific challenges.  

The usual approach by pharmaceutical companies is to design — or to obtain the rights to — a novel inhalation device, which can preferably be used for a wide range of different drugs, concentrations and applications. The DPI products are then typically developed using iterative processes, that is, formulations are based on empirical studies (albeit ones informed by experience) until satisfactory DPI performance and blend characteristics are achieved.  

One important aspect of this approach is the tailoring of the carrier material to the required formulation and device characteristics. This can ideally be achieved by using 'as supplied' or 'off-the-shelf' samples of lactose.  

Alternatively, such samples could be processed by the user to produce carriers with the required characteristics. Increasingly, lactose manufacturers are supplying customer grades that are produced to a tailored specification, which might result in supplier/user issues.  

In terms of pharmaceutical drug delivery, DPI carrier technology can be considered a low dose system, which poses challenges both to formulators and, consequently, excipient suppliers. This is exemplified by the fact that a drug dose of 200 μg is considered a relatively 'high' dose in DPIs, and yet this can correspond to <1% drug concentration in the blend; for example, Miflonide (budesonide); Ventolin, Pulvinal (both salbutamol); and Seretide (salmeterol/fluticasone).

Additionally, carrier-based higher potency medications exist that require even lower doses (for example; Foradil, formoterol fumarate, 12 μg, ~0.05% drug load), posing obvious formulation and analytical challenges.  

In terms of DPI formulation development, any carrier for DPI applications should ideally be: 					

 fully characterizable for parameters known to be crucial for performance 

 stable (crystalline and not contain any uncharacterized metastable structures) 

It is difficult for any excipient to meet these criteria and, as with many excipients, there are still questions concerning true physicochemical characteristics, and importantly, their effect on DPI characteristics. Additionally, there are still questions concerning supplier and user characterization methodologies. 

Lactose DPI carriers are commercially available from several sources (Table 1). The volumes of lactose manufactured for this application are very small compared with those used for oral applications.  

 Table 1 Lactose and inhalation grade lactose suppliers.			

However, in such a specific 'technology platform' the excipients provide significant technical and financial challenges to suppliers and users because they will require greater product and regulatory scrutiny for consistency and quality than would be expected for comparable products in general tablet and capsule applications. 

The potential issues concerning any DPI excipient can be generally divided into physicochemical characteristics and residues. 

It is possible to describe lactose monohydrate products in terms such as particle size, shape factors, roughness, moisture sorption, surface area and surface energy, among other parameters. 

However, the exact relationships between such descriptors and functions are, as yet, not fully understood and there is continuing research by the pharmaceutical industry to investigate the relationships between such characteristics and DPI performance. 

 As with all aspects of pharmaceutical development, there are questions concerning excipient (and drug) intra-batch, inter-batch and inter-supplier equivalence. The effect of any such variations in pharmaceutical applications will depend on the robustness of the drug delivery vehicle and formulation specifications. Consequently, any subtle changes in lactose monohydrate powder properties (e.g., particle size distributions and surface roughness) may have dramatic effects on formulation performance, with obvious product and regulatory implications if the product is not sufficiently robust (e.g., one that has not been developed to meet 'Quality by Design' criteria, to accommodate those changes). 

 There are many ways to describe a powder in terms of its particle size distribution (PSD). Particle size descriptors are important at the manufacturing (supplier) and formulation (user) stages of pharmaceutical development. In terms of suppliers, specific PSDs are produced by sieving or classifying. While both methods have different inherent effects on the PSD, for example, in terms of size cut-offs, they can both be used to produce powders with suitable PSDs.

The PSDs, in terms of a product descriptor, can be characterized by suppliers and users by laser light diffraction. It is important that PSD measurement methodologies employed by suppliers and users are consistent and, importantly, validated and understood. This not only includes the actual methodology, but also sample handling procedures and sampling frequencies. 

 Lactose can exist as alpha–monohydrate, beta–anhydrous, stable alpha–anhydrous, unstable alpha–anhydrous and a 'mixed crystal' of anhydrous alpha and beta lactose. Depending on environmental conditions, lactose can also be stable in an amorphous state.  

It can be argued that any excipient used in solid dosage forms, including any ideal carrier for DPIs, should be stable (within known parameters) during the stability claims of the product. Therefore, the presence of any metastable material in the carrier, in particular in the surface of the carrier particles, may be a source of formulation variability, particularly for low dose products. In terms of stability, lactose monohydrate is crystalline and the most stable. All the forms of lactose can be described from a strictly physicochemical viewpoint as metastable; they all revert to lactose monohydrate depending on storage conditions and time. In general, there are analytical techniques available to quantitatively assess the presence of these forms. However, the current analytical limit of about 1–2% may not be sufficient to adequately characterize the bulk and surfaces of the excipient.  

 The subjection of organic materials to mechanical stress can result in the formation of an amorphous material. The amorphous contents of milled and sieved grades of commercially available lactose monohydrates, including DPI grades, have been reported to be 1–4% and <1%, respectively, determined by differential scanning calorimetry or microcalorimetry.

  Obviously, such metastable sites will have different interactions with drug (and excipient) particles than 'stable' crystalline regions.  

Since amorphous lactose can crystallize instantaneously above a water activity of approximately 0.5 at room temperature, there must be questions concerning the physicochemical composition of DPI lactose monohydrates, both when supplied, and during the DPI formulation and product life cycle. 

 Anhydrous lactose can be present at low levels in lactose monohydrate, for example, by crystallization of amorphous lactose — the level of which depends on the crystallization conditions.

  It is metastable and reverts to lactose monohydrate at high water activities over relatively long time scales. Raman microscopy of crystallized amorphous lactose suggested that domains of beta lactose were present in the crystalline surface.

The excipient anhydrous lactose as used in certain inhaler formulations is a good example of the potential difficulties encountered when considering the relationship between purity and pharmacopoieal acceptance — since there is no compendial limit on anhydrous alpha and beta levels posing obvious manufacturing and characterization challenges.  

 The presence of very low levels of residues (including solvents) in excipients is becoming an important issue for users, and the presence of very low levels of Â´non-lactoseÂ´ species in DPI lactose may pose challenges to suppliers and users. Such components are present because of use of the natural product milk, and the manufacturing processes involved in the production of lactose. 

 Lactose, like many excipients, is derived from natural sources, in this case the whey from milk. As with other excipients derived from natural sources (such as microcrystalline cellulose and starch), it would be expected to contain natural 'impurities'. For example, in terms of pharmaceutical applications, the issue of the presence of proteins was recently highlighted by a report that milk proteins have been identified in DPI products.

  Allergic reactions to products containing milk proteins have been reported in patients with a severe milk protein allergy.  

There is no specific assay for proteins/peptides in the monographs for the different polymorphs of lactose. Nevertheless, the monographs describe solution absorbance tests. Of these, perhaps the test for absorbance at 400 nm is a good indicator of protein levels, since absorption at this wavelength is an indication of the degree of protein-based chemical reactions such as the Maillard reaction, an obvious source of potential stability problems.  

Currently available techniques to directly determine the content of proteins in lactose (e.g., via nitrogen determination by Kjeldahl) may, as an analytical technique focusing on the bulk and not on the surface, not be specific enough to sufficiently reflect the influence these impurities may have on the performance of the resulting product. Investigations using X-ray photoelectron spectroscopy (XPS) indicated that up to 1% of atoms in the top 10 nm layer of a specifically produced DPI lactose are nitrogen in the peptide configuration.

  This may indicate a level of up to 10% for peptide impurities in the surface areas.  

The effect of such high levels of these impurities on apparent DPI performance has yet to be determined, but may be important for the performance of any potential protein-based DPIs since these proteinaceous materials may be capable of changing the apparent aerosolization or product stability; for example, in milk powders the Maillard reaction and oxidation are reported to enhance protein interactions.

Lactose as a natural bovine product, derived from cow's milk, which is manufactured by the aid of calf's rennet (or by biotechnologically manufactured Chymosin) might be considered to be a potential risk factor to transmit BSE (bovine spongiform encephalopathy) infectious prions. However, according to the Guideline EMEA/410/01 Rev. 2 "milk...is unlikely to present any risk of TSE (transmissible spongiform encephalopathy) contamination...", irrespective of the geographical origin (and, therefore, to comply with the guideline), provided specific risk reduction factors are being met. Although milk is unlikely to present any risk, the theoretical residual health risk may be further reduced by sourcing the milk from countries thought to be free of BSE and/or by choosing lactose which was manufactured with the aid of biotechnologically engineered Chymosin (to avoid usage of calf's rennet).

The adoption of The International Conference on Harmonization (ICH) Quality 8 (Q8) could represent a milestone in the way that pharmaceutical products are developed and chemistry and manufacturing control (CMC) sections are accepted by worldwide regulatory agencies.

  The text of this guideline states "those aspects of drug substances, 

, and manufacturing processes that are critical and that present a significant risk to product quality, and therefore should be monitored or otherwise controlled, should be identified and discussed".  

ICH Q8 formalizes the ideas of 'Design Space' so that products are better understood and that product failures are less frequent. An important and welcome feature of the development paradigms that this guideline formally introduces is that it is the quality of the data developed that should be important, rather than the quantity of data.  

It can be argued that any of the performance factors noted above could have a significant influence of the performance of a DPI, and thus a sensible design of experiments for a lactose–based DPI product could include, amongst others

 Multiple batches of lactose (perhaps sourced at different times of the year). 

The presence of very low levels of residues (including solvents) in excipients is becoming an important issue for users, and the presence of very low levels of ?non-lactose? species in DPI lactose may pose challenges to suppliers and users.