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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.
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).1
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:
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.
Physicochemical characteristics. 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.
Batch variations. 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).
Particle size distribution. 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.2
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.
'Polymorphism'. 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.
Amorphous content. 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.3 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. 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.4 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.5
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.
Carrier residues. 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 manufacturing residues. 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.6 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.7 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.8
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).9,10
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.11 The text of this guideline states "those aspects of drug substances, excipients , 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
Any DPI formulator decisions, for example, to utilize a custom grade of lactose, perhaps by sieving, would have to demonstrate that the fraction chosen (e.g., 63–90 and 90–125 Âµm are commonly chosen for DPI development) is superior to the parent material and other possible size fractions. It would be necessary to check whether the custom grade of material performed better with or without fines by, for example air-jet sieving the fraction.
The addition, or re-addition of fines or ternary agents would lead to a further design of experiments that took into account ratio of fines or ternary agents to carrier; varying amounts of amorphous contents within the fines; and characteristics of fines or ternary agents produced by different routes. The whole range of design of experiments may have to be performed at a range of manufacturing and testing environments, to mimic conditions that might pertain throughout possible manufacturing sites and countries where the product might be prescribed.
The same will apply to DPI formulations. Each component, ratio and nature of component will not be justified by the instinct of the formulator, but will have to be borne out by robust data. An important part of ICH Q8 includes the necessity to "justify the choice and quality attributes of the excipient". This, once again, puts a burden on the formulator to develop a close relationship with the excipient supplier. Other external factors may, nevertheless, derail the formulator/supplier relationship and whilst the choice of lactose supplier for the long term (which is what ICH Q8 implies) may take all currently known parameters into account at the start of development, the discovery of issues may require rethinking and, perhaps, significant formulation effort.
In terms of regulatory acceptance, lactose monohydrate, and excipients in general, are described by monographs in the pharmacopoeias. Additionally, the special case of inhalation lactose is highlighted with the advent of a specific United States Pharmacopeia (USP) monograph. This blanket approval does not imply that the excipient will offer universal functionality.
Ideally, lactose suppliers and drug manufacturers should produce consistent carrier and drug products. Increasing the washing and crystallizing stages and improved controls during drying will reduce protein, polymorphic/solvate type impurities, and variability in particle shape and surface structure.
Nevertheless, in some cases, materials may exhibit similar characteristics, but unexplainable formulation differences. The improvement of powder and material characterizations will reduce potential issues during development and scale-up, especially if such methods are developed in partnership with users' sampling and particle size methodologies.12
Many studies have described the relationships between formulation performance to carrier characteristics and functionality. Some general observations concerning particle size and so forth, have been reported. However, it should be remembered that any tailor made lactose for a specific study will have different characteristics and impurity levels than commercial grades, which may affect the formulation performance.
In terms of the future, it has been suggested that pharmaceutical manufacturers should work in co-operation with their excipient suppliers to ensure they have a detailed understanding of all aspects of the excipients.15 For DPI excipients, it would be advantageous if manufacturers and users develop universal and accepted product characterization methodologies, which may help reduce the problems associated with inter- and intra-batch variations.
J. Sebastian Kaerger is principal scientist at Novartis Pharma AG, Inhalation & Device Development (Switzerland)
.Robert Price is a reader in the Pharmaceutical Surface Science Research Group at the University of Bath (UK).
Paul M. Young is a lecturer in the Advanced Drug Delivery Group at the University of Sydney (Australia).
Stephen Edge is a visiting scientist in the Pharmaceutical Surface Science Research Group at the University of Bath (UK).
Michael J. Tobyn is a visiting lecturer at the University of Bath (UK).
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