It has been more than a hundred years since Bordas and d'Arsonval demonstrated that a fragile substance could be stabilized by drying its solution from the frozen state. Additionally, for more than sixty years, lyophilization has been used extensively to prepare instant human plasma. Antibiotics, steroids, and bacterial and virus vaccines have also been prepared through freeze-drying by pioneers including Flosdorf, Greaves and Henaff. 

Today, despite a somewhat depressed market in the early 1970s because of the development of pure, stable crystallized chemicals, lyophilization is still an almost unavoidable technique when preparing delicate proteins, complex immunological factors and sensitive products resulting from genetic engineering. Many different laboratories are engaged in this research and they often face rather difficult issues. Five of these key areas are discussed in this article. 

Most products cannot be dried because they are either in very small amounts (per therapeutic unit) or because they need some kind of "protection" during the different stages of the process. Product formulation is thus a fundamental issue and requires the appropriate optimum association of cryoprotectors, bulking agents, moisture stabilizers and co-solvents. Quite obviously, the great number of different "formulations" that result from these studies deserve specific case by case investigations to determine — at the experimental and pilot levels — ad hoc freeze-drying cycles since there are no all-purpose recipes available. An interesting alternative to bulking agents could be the adsorption of the active substrate on a neutral porous substrate from which it is extracted at the time of reconstitution. 

As most freeze-dried products are used as injectables, it is compulsory to avoid their contamination during processing to ensure their sterility and prevent the presence of undesirable micronic or even sub-micronic particles.  

Accordingly, a substantial amount of research has been devoted to developing special glassware, devoid of any surface contaminant and having quartz-like, non-adsorbing internal walls (e.g., Type I Plus [

]) as well as new polymer vials resistant to heat-sterilization. Another interesting approach has also been initiated by GORE with the introduction of sterile containers for bulk-drying sealed with water vapour permeable membranes,  which are impermeable to bacteria and micronic particles (Lyoguard [

The ever growing size of freeze-drying operations results in the need to conduct large-scale operations, involving tens of thousands of vials, making it necessary to use automation. Equipment manufacturers as well as pharmaceutical operators have developed clever and reliable designs for automatic filling, loading, unloading, capping and final release of the finished products. 

Regulatory authorities require full and appropriate validation of the freeze-drying process. The major issue relates to sterility at the end of the drying cycle, which can never be taken for granted when dealing with batches of 100000 or more vials in several multi-shelf freeze-drying cabinets. Recently, radiation has been introduced as a way of ensuring absolute sterility. This includes cobalt-based gamma irradiators, a new generation of powerful, high-voltage electron-beams and high-energy X-ray units.  

Another major issue is the control of the residual moisture in the plug. A full range of different instrumentation may be used including classical Karl Fischer determination of chemical water thermogravimetry, nuclear magnetic resonance, near-infrared technology and, more recently, non-invasive water vapour pressure measurements.  

Optimum residual moisture should always be achieved and it depends entirely on the product. Some freeze-dried preparations need to be on the very low side (0.1%) while some others require a much higher value (5% or more) to avoid denaturation of the tertiary structure of sensitive proteins, which must not lose their constitutional water-content. 

In view of the nature of its complexity, it might be desirable to apply FDA's process analytical technology (PAT) to lyophilization.  

PAT could be applied in many segments of the freeze–drying cycle, which could then be controlled and monitored on-line (e.g., filling, loading, unloading and capping.) It is, unfortunately, much more difficult to effectively implement PAT in the heart of the process — drying under vacuum — since this is a unit operation where direct access to representative samples of product is difficult.  

This does not mean, however, that it is impossible, but special equipment will need to be developed. It is a challenging issue and, as we proposed several years ago, the solution may lie within the use of semi-continuous to continuous operations, which are common practice in the food industry (e.g., instant coffee).  

A continuous freeze-dryer, coupled with both on-line conditioning equipment and a final post-sterilization irradiation unit (also on-line), could be the answer to successfully implementing PAT.  

This is a challenge for all parties and  requires close collaboration between equipment manufacturers, freeze-drying operators and compliance officers so that regulatory requirements remain in line with technical and economical possibilities.  

If we add, on top of these issues, the possibilities offered by the use of organic solvents or co-solvents in formulation, and even the potential application of selected mineral solvents such as NH

, we see that lyophilization remains a very important technology.  

 is scientific advisor at the AERIAL Technological Resources Center, Illkirch (France).			

 is manager of pharmaceutical operations, Innate Pharma, Marseille (France).			

Articles

Manufacturing & Processing

In view of the nature of its complexity, it might be desirable to apply FDA's process analytical technology to lyophilization.

Lyophilization is not a freeze-dried technology

The potential for innovative technology in healthcare and the commercial applications of bioscience is huge: the bioscience and healthcare sectors in the UK generated over €34 billion during 2004, of which €17.75 billion was directly from the pharmaceutical industry and €16.25 billion was from medical devices.  

Clearly, major advances in science and technology are fuelling the globalization of the world's markets. The trends of an increasingly ageing population; increasing demand for — and costs of — healthcare provision; and the spiralling costs of drug development are global. As a consequence, companies need to constantly strengthen their capabilities and find innovative ways to satisfy customer demands and UK organizations have significant market opportunities.  

To ensure that UK firms remain at the forefront of technology development and exploitation, it is vital that businesses can identify potential commercial applications for the promising new technologies emerging from the country's research community.  

The UK Government's 10-year science and innovation investment framework leads on this agenda and aims, through an investment of €5 billion, to ensure that the potential to turn innovation into commercial opportunity is maximized.  

Until recently, the Office of Science and Technology and the DTI's Innovation Group have worked together to successfully deliver the framework in a highly successful partnership. Now they have come together into one organization. The DTI's Office of Science and Innovation (OSI) continues the commitment to make the UK one of the best places in the world for science, research and innovation.  

OSI's challenges to achieve that vision include sustaining and developing the UK's world-class research base, strengthening its links with business and other users, enabling knowledge transfer, and promoting innovation in products, services and processes. 

It works closely with the business-led Technology Strategy Board (TSB), which advises the Secretary of State for Trade and Industry on business research, technology and innovation priorities for the UK, the allocation of funding across these priorities and the most appropriate ways to support them.  

Since October 2004, the board has engaged business, the research community and other stakeholders in identifying key technologies where the UK has the potential and opportunity to lead the world — and both the strategy and the board have achieved international recognition for their work in developing UK innovation policies.  

The board oversees the Technology Programme, which supports companies by sharing some of the financial risk of their medium- to long-term investments in technology. Through its business-driven framework and an investment of €547 million over three years, it supports competitions for collaborative R&D and is establishing knowledge transfer networks (KTNs) intended to enhance the UK's competitive position.  

This year has seen the launch of a number of KTNs, which will provide a range of support services, including a dedicated website, business-to-business facilities, networking opportunities, online conferencing, briefing notes, and expert opinions on technology and policy.  

Today, the board is developing a strategy for UK wealth creation and is calling on business to help realize its vision. In April this year, it launched six medium-term strategies in key technology areas, all of them developed in consultation with business and all of which the board felt can generate new streams of economic activity in their own right.  

It also invited business to share its thoughts by engaging with the strategy and contacting the board with its views on priorities, issues and future direction. Individual businesses were also urged to become involved, with the board emphasizing that business and the board need to work together to develop a more market-oriented, holistic approach to meeting the needs of the UK's world-leading industries.  

Moving forward, it is also important that we align with technology strategies at a European level, in particular the Innovative Medicines Initiative, whose main objective is to remove the bottlenecks hampering the efficiency of new medicine development — thereby providing faster access to better medicines for European citizens. This will also ensure that the UK is in the best possible position to take advantage of opportunities under Framework Programme 7, the EU's chief instrument for funding scientific research and technological development.  

Science and innovation is vital for the future of the UK economy. UK science has an outstanding record and remains strong internationally in terms of achievement, productivity and efficiency. The amount of business investment in R&D must increase if the UK is to remain competitive in an increasingly global marketplace. It is essential that business helps to drive the technology strategy forward. 

For further details of up and coming Collaborative Research and Development Competitions, visit 

www.dti.gov.uk/innovation/tech-priorities-uk/index.html

 is director of science and innovation at the Department of Trade and Industry, UK.

R&D News

UK science has an outstanding record and we remain strong internationally in terms of achievement, productivity and efficiency.

Science and innovation is the UK's future

Mefenamic acid (MA) [N–(2, 3–xylyl) anthranilic acid] is a high-dose, non-steroidal anti-inflammatory agent available in immediate-release capsule and tablet formulation. It is poorly soluble in aqueous media, sticking to any surface, creating problems in granulation and tabletting processes.

				 Mefenamic acid shows bioavailability ranging from 28–86% in capsule form. 

The difference in bioavailability was found to be a result of the variation in dissolution rate involving multiple factors, such as the particle size and packing of the drug, and the de-aggregation rate of MA.

  Our studies revealed that MA from different manufacturers has different crystal properties. The complete solid-state characterization of MA has also been performed.

  We found that crystallization of MA from ethyl acetate (EA) at a fast cooling rate generated a new crystal form (or a crystal defect). To explore the feasibility of preparing this new polymorph, this study was conducted by altering the polarity of EA with different organic solvents under various crystallization conditions.  

Ethanol (E), EA and tetrahydrofuran (THF) were of absolute, analytical and HPLC grade, respectively.  

 Potassium bromide (KBr) used for recording Fourier Transform infrared (FTIR) spectra was FTIR grade. 

. Recrystallized samples of MA were viewed/photographed under light and polarized light microscopes at various magnifications (×10, ×25 and ×45).			

MA samples recrystallized from various solvents at varying degrees of supersaturation, cooling rate and agitation speed were screened for the required polymorph under a hot stage microscope (Leica DMLP; 

) at a constant heating rate from 32–250 °C to observe any transition.  

 The surface morphology of MA-recrystallized samples was studied using an SEM (D–6000; 

). Samples were fixed on a cylindrical aluminium stub with conductive double-sided adhesive tape and sputter-coated with gold.  

 Thermal analysis of MA samples was recorded in a differential scanning calorimeter (DSC 821; 

) using Mettler STARe software with the Solaris operating system (version 5.1).  

Samples of 1–5 mg were weighed directly into aluminium crucibles sealed with pin-holed lids and scanned at 25–300 °C with a heating rate of 10 °C/min under nitrogen purging (80 mL/min). The temperature axis, heat flow and cell constant were previously calibrated with a pure sample of indium. An empty aluminium crucible sealed with a pin-holed lid was taken as the reference cell. 

 This was performed on the weighed quantities of samples by heating from 25–300 °C at the constant rate using a thermogravimetric analyser (

). Any weight loss occurring before the melting point of the drug can be a result of solvent residues occluded in drug crystals during recrystallization.  

A pellet was prepared by mixing 2–5% of the sample with KBr using a mortar and pestle, and compressed at a pressure of 15000 psi. Spectra were recorded in the transmission mode in the region of 4000–4500 cm

 To minimize preferred orientation, all samples were prepared by passing through a sieve (number 60) for pXRD analysis. The pXRD pattern of recrystallized samples was recorded at room temperature using an X-ray diffractometer (

) with Cu kα1 radiation operated at 350 kv. Diffractograms were recorded over an angular range from 5–50° 2θ in a continuous scan mode using step size of 0.04° 2θ and a step time of 0.5 s. 

Intrinsic dissolution rate (IDR) studies. 

IDR studies of recrystallized samples were performed using rotating disc apparatus with optimized parameters such as sample weight, compression force and stirring speed. Sample powder weighing 100 mg was compressed using a hydraulic press at a force of 3000 psi for 1 min to yield pellets of surface area 50.27 mm

  that would not disintegrate during the test.  

Study conditions include a 1000 mL jar, containing 900 mL of borate buffer maintained at 37 °C and 100 rpm. A sample volume of 5 mL was withdrawn at specific time intervals and analysed for MA.  

 Equilibrium solubility of MA acid was determined in two solvent mixtures EA:E (10:90% v/v) and EA:THF (50:50% v/v) at 32 °C and 60 °C. The drug was added to 5 mL solvent mixtures (kept in vials) until no more drug was dissolved at the specified temperatures, and closed with aluminium foil and rubber caps to prevent vaporization. All solutions were kept under constant stirring at 100 rpm at constant temperature in a water bath (

). At set time intervals, a fixed amount of solution was withdrawn with a microlitre syringe (

) and analysed by UV-vis spectrophotometry at 280 nm (DU640i; 

Recrystallization of MA was performed from various solvents with differing degrees of supersaturation, cooling rates and with or without stirring. For recrystallization, the crystallizer was designed by using a 500 mL beaker jacketed with a 1000 mL beaker, whose inlet and outlet were connected to a circulator water bath (

) capable of controlling the temperature to 0.1 °C/min. Both the inner beaker containing sealed ampoules and outer beakers were closed separately.  

Recrystallization was performed in sealed ampoules containing magnetic beads and 15 mL drug solutions of varying concentrations in different solvents. The entire crystallizer containing ampoules was placed on a magnetic stirring plate and the temperature increased to 70 °C, at which point all the drug in ampoules was solubilized. Cooling was then performed at slow and fast rates with the aid of a circulator bath, with and without stirring. The crystals were filtered and dried in a dessicator for 12 h. 

To study the effect of harvesting time on polymorph generation, crystals from drug solutions of EA were filtered at two different times, and a visible mass of crystals was seen in solution after fast cooling. The crystals were kept in a dessicator for 12 h and analysed. 

Solvents showing less solubility and high solute–solvent interactions are preferred for metastable polymorph generation.

  Furthermore, an appropriate balance between solubility, and hydrogen bond donating and accepting propensity of solvents is necessary.  

MA solubility increases with decreasing polarity of solvent and has very high solubility in THF; therefore to achieve a balance between solubility and solute–solvent interactions, mixtures of solvents were prepared (THF:EA [50:50% v/v]; E:EA [90:10% v/v]). 

The generation of a metastable polymorph was demonstrated in a previous study of EA at different recrystallization conditions (i.e., the degrees of supersaturation were 50.25 mg/mL, 53.00 mg/mL and 55.75 mg/mL, and the cooling rate was 20 °C/h with stirring). 100% EA was also selected for recrystallization.

MA equilibrium solubility was determined at 32 °C and 60 °C in two solvent mixtures using a shaker water bath. The equilibrium solubility of MA increased with decreasing solvent polarity, as expected, at both temperatures. In addition, equilibrium solubility at 60 °C was determined to decide the degree of supersaturation for recrystallization experiments, while 32 °C was used to calculate the theoretical yield of recrystallization.

Characterization of recrystallized samples.

Recrystallization of MA was performed in solvent–solvent mixtures (E:EA, EA and THF:EA) of three different polarities at three degrees of supersaturation and two cooling rates, with and without stirring. HSM and DSC screened all the crystals for new crystal properties and polymorphic forms. However, a significant difference in recrystallized product with respect to solid state was observed only in crystals obtained from E:EA mixture at various recrystallization conditions. 

These crystals were further characterized by additional techniques to confirm the existence of the new polymorph. 

All crystals were observed under light and polarized microscopes to identify any change in morphology as well as optical properties. Since all the samples showed birefringence under a polarized microscope, the possibility of the amorphous form being produced at a fast cooling rate was ruled out.  

There was a marked difference in the size of crystals obtained under different conditions where crystal size increased with decreasing cooling rate, unstirred conditions and increased degree of supersaturation. Some surface grooves were also seen for THF:EA and EA-recrystallized samples.  

Crystals from EA and THF:EA showed a wide transition range of about 10 °C between 150–215 °C, without recrystallization. Other than this, samples recrystallized from EA with the shortest harvesting time did not show any transition before melting. There was a sharp melting of crystals obtained from E:EA under stirred conditions at 222 °C while the melting point of MA is 231 °C (Figure 1).  

 Figure 1 HSM of crystals from E:EA under stirred conditions. All the crystals showed a sharp melting between 220â223 Â°C.			

Furthermore, the melted product recrystallized at 223 °C and could not be seen clearly since melting and recrystallization were almost simultaneous.  

Melting without any transition appears to be caused by too high a heating rate. The sharper melting and recrystallization events of crystals from E:EA can be attributed to melting at 222 °C, followed by recrystallization at 223 °C leading to melting at 231 °C. A similar trend of solid–liquid transition was also observed for carbamazepine, which melted at 175.92 °C, recrystallized at 181.66 °C and melted at 192.1 °C.

The wide transition of crystals from EA and THF:EA is representative of solid–solid transition. This was observed at 150 °C for solid–solid transition of monoclinic retinoic acid to its triclinic form followed by its complete melting at 183 °C.

However, a different trend in transition and melting of recrystallized product from the E:EA mixture and other solvents indicated the possibility of a different crystal form. 

In light microscopy, some grooves were seen on the crystal surface of samples from THF:EA and EA compared with those from the E:EA and the United States Pharmacopeia (USP) reference sample, hence SEM photomicrographs of representative recrystallized and USP reference samples were recorded. The reference sample was observed to be an aggregated microcrystalline mass with columnar plate-like properties.			

Formulation

Mefenamic acid has variable bioavailability and tabletting issues because of its hydrophobic nature and poor material characteristics. Recrystallization of mefenamic acid was performed from three different solvent–solvent mixtures under differing conditions. The crystals obtained were screened for the existence of new crystal properties or polymorphic forms, then characterized further.

Mefenamic acid: new polymorph or crystal defect?

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.

Carriers for DPIs: formulation and regulatory challenges

Developed in the 1950s as a means to survive and compete against the giants of the automotive sector, lean manufacturing helped Toyota evolve from a small-volume producer (with little capital) to become a high-volume manufacturer in a process-rich environment. Toyota achieved this by using developments such as total production maintenance (TPM), just-in-time (JIT), Kanban, value stream mapping and Kaizen events.

  A summary of some of the lean terminology is shown in Table 1. 

 The pharmaceutical industry, manufacturing in a current good manufacturing practice (cGMP) environment, has been slow to adopt lean manufacturing — unlike many sectors where it has been successfully deployed. This article attempts to compare these two manufacturing environments and identify areas of overlap, together with challenges pharma may face in moving towards lean manufacturing. 

GMP has evolved gradually, however the recent scientific risk-based framework and the process analytical technology (PAT) initiatives, developed by regulatory authorities to support innovation and efficiency in a cGMP environment, suggest a new way of thinking for the 21st century.

Since 2001, regulatory authority policies have promoted initiatives designed to increase the availability of new and affordable medicines. This new thinking should help the pharmaceutical industry move towards innovation in manufacturing and alleviate the fear of lean improvement. These fears will only be removed when manufacturers are confident that a successful lean implementation in a cGMP environment can have both regulatory approval and be technically dependable.  

A comparison of cGMP with lean manufacturing (Table 2) might suggest that they belong to two conflicting families. 

Table 2 A comparison of lean and GMP manufacturing.			

While cGMP focuses on manufacturing as a means to produce safe and effective products for the patient, lean focuses on manufacturing as a location for improvement and value creation from a customer's perspective. For example, the public's expectation for an aspirin tablet has changed very little in comparison with their expectation for a personal computer during the last thirty years. They still expect the tablet to be safe and effective, while they expect the computer to have improved and provide greater value in return for the price paid. 

Lean's dual objectives, to reduce or eliminate waste and to create value, differ from cGMP's objective, which is to ensure that controls are in place to deliver a safe and effective medicinal product. Perhaps where cGMP and lean do overlap is in a shared history in the control of the manufacturing environment. To see the degree of overlap, a new perspective of lean, referred to as lean pharma, will be discussed.  

Lean pharma can best be viewed by looking across the lean landscape from a cGMP perspective. To do this, one has to define in simple terms what "lean" means.  

 In 1999, Spear and Bowen identified four rules that describe the make-up of the lean manufacturing system

 Standard work — all work must be specified as to content, sequence, timing and outcomes. 

 Clear relationships and communications — every internal customer-supplier connection must be direct with unambiguous ways to send requests and receive responses. 

 Simple flow — the pathway for every product and service must be simple, direct and followed. 

 Scientific method — improvement should be made using scientific methodology, under the guidance of a teacher and at the lowest possible level in the organization.

They identified the lean manufacturing paradox; the existence of rigidly documented processes that operate in a flexible and adaptable environment. It is the combination of being able to perform the simple things right, while also having the ability to change and adapt to customers' demands, which makes lean such a successful improvement methodology and business survival tool. 

For the purpose of this article, it will be assumed that these four rules must be followed for a traditional manufacturing culture to reach the tipping point to transform into a lean manufacturing culture.  

 One of the characteristics of a cGMP manufacturing environment is the abundance of documented processes such as standard operating procedures (SOPs), testing methods, environmental controls and training programmes. This documentation can be divided into technical standards and operational procedures. 

Technical standards, such as product specifications, validated settings and production conditions, can only change following a change control exercise. Operational procedures, such as the way people interact with equipment and the way that product flows, are based on custom and experience, and will change regularly in response to deviation or safety concerns. 

The essence of lean pharma is determining how current operational procedures can be modified to support short-term improvement, while maintaining the technical standards — thus ensuring no risk to the product. An attempt is made to do this, from a cGMP perspective, for each of the four rules defined here. 

Standard work in lean manufacturing is an agreed set of work procedures that establish the best and most reliable methods and sequences for each process and employee.

  It is a detailed instruction on how a task can best be performed today, with the understanding that it can be improved tomorrow. 

Standard work procedures are communicated simply and easily; more chart and display than paragraphs and pages. The employees who work with the process write the standard work procedures and their descriptions reflect what actually happens in the work place rather than what might happen. It is written after the manufacturing step has been optimized to ensure product quality is reproducible and product flow is continuous. 

Standard work is desired because if you can standardize a process then you can control it; and if you control it, then you can improve it. This is the essence of this rule. 

 In lean manufacturing, every step in every operation is performed in a predictable manner. The time, sequence, outcomes and inventory levels for each step are specified. The work time to perform a task is independent of the operator, so if it changes (increases or decreases) a problem has occurred. This immediately alerts the team leader to a problem as it happens, thus ensuring real–time control. 

Looking at the pharmaceutical industry, it may appear that standard work is already 

, with SOPs, manufacturing instructions, testing methods and validation protocols. However, these documents are often written by team leaders or scientists following validation and are only updated in response to a deviation, safety or quality issue.  

In the cGMP environment, critical specifications and technical standards are very well defined, deviations from which are obvious and thus action can be taken. Operational procedures, however, are often light on detail and as a result, variations in these may not be detected. For example, the way an operator sets up a workstation may vary with respect to time and outcomes. A check sheet may ensure that critical steps have been completed, but the manner in which the end-result was achieved is not obvious. It is then possible for work variation to enter if people use slightly different methods to achieve the same result. Typical finished dose manufacturing instructions may include "charge the blender...", "set up take-off plate".  

In a lean pharma plant, SOPs and other manufacturing instructions would be viewed as a means to expose problems and encourage improvement. Technical standards will be identified and fixed in line with regulatory requirements; all other operational procedures would be reviewed on a systematic basis and standardized with respect to time, sequence, content and outcome. For example, the batch manufacturing instruction could still contain the term "charge the blender", but the work standard for the blender would be written by the people who perform the action and would appear in a separate form, possibly as a chart or on-line display.  

The challenge for the pharmaceutical industry in moving towards lean is to design new operational procedures that comply with all external regulatory requirements, but at the same time support continuous improvement. 

In the lean manufacturing environment, every customer-supplier connection is direct with unambiguous ways to communicate. There is a clear and agreed way to send requests and receive responses. Product and information flows from one department to another and the barriers between departments are reduced. The overall goal is to keep product flowing. Consistent cycle time is an indicator of good internal supplier-customer relationships.  

In the cGMP environment, product cycle time is quality driven; it may take longer to release a batch than it does to produce it. Different departments usually have clear individual responsibilities and objectives. Departments often have separate responsibilities and objectives, resulting in teams working in isolation or in conflict with one another. Individual departments are often unaware of the impact that their delays or problems have on overall product flow.  

In the lean pharma environment, cycle time and quality would be of equal importance. This overlaps with FDA's PAT framework of reducing production cycle time. When a deviation in cycle occurs, it may indicate potential quality issues. For example, if it typically takes an operator 40 minutes to set up a tablet press but a batch takes longer, this indicates a problem with that batch. In lean pharma, a request for help would be made by the operator at 41 minutes, thus commencing an investigation. 

The need to ask for help when product flow is interrupted may lead to the identification of quality issues that otherwise might have been hidden from view or only detected during final release. For example, when an operator in a traditional pharma plant is required to produce a tablet to a specified disintegration time, the time it takes to set up the tablet press to produce tablets meeting the required technical standard is not controlled. In a lean pharma plant, the operator would have a work time standard. If it is not possible to produce the tablet to the required disintegration specification within this time, a call for help would be made. This may expose a problem in the upstream process, in this case granulation, which would otherwise be masked.  

The challenge for pharma in moving towards lean is to reduce the grey zones of responsibility, slow response and late calls for help when problems occur, and move towards an environment where problems are immediately identified, shared and resolved across the plant. 

In lean manufacturing, the pathway for every product and service must be simple and direct. Simple in that there is only one way to move forward and direct in that there are no loops, forks or fast paths.  

In the cGMP environment, the product path tends to be direct but far from simple because of batch manufacturing. This batch production method is inherent in cGMP to prevent cross-contamination. Each process step usually has a holding time for work in process, thus encouraging intermittent flow. Typically, a pharmaceutical facility operates with surplus capacity to keep the product moving, rather than flowing; however, this operational mode obstructs simple flow. For example, when a batch of tablets is scheduled to run on a blister pack line and three lines are available, surplus capacity at packaging exists. This will hide the reasons for any excessive downtime and slow changeover on the lines.  

Having available surplus capacity does not encourage continuous improvement or problem identification. From the customer's perspective, the fact that a pharmaceutical plant is running with surplus capacity should have little consequences in the short-term. The product will still be delivered on time, at the right quality and in accordance with cGMP, but the plant with surplus capacity available has higher operating costs.  

In the lean pharma plant, product or services would not flow to the next available person or tool, but to a specified person or item of equipment. This rule enforces the economies of repetition — the more times you take a certain path the more familiar you are with that path. Each time the product takes the same path, an experiment will occur to uncover variation and expose problems. This encourages continuous learning over the life cycle of a product. 

A batch moving from manufacturing to finished goods would only slow down for a value adding step. There would be a continuous programme to reduce batch queues and a move towards small-scale equipment to improve efficiency and manage variability. In lean pharma, the focus would be to reduce your batch size, move towards single unit flow, and thus improve responsiveness to changes in customers demand.  

The challenge for pharma in moving towards lean is to introduce simple flow for products and services and expose areas where improvement in flow will reduce cycle time and cost. To move forward from batch manufacturing towards single unit flow.  

The first three rules are rules of design, which show how to set up operations as experiments, with a view to controlling the process and ensuring it is reproducible. The fourth is the rule on improvement. Once you can do the job consistently every time, then you can improve. Attempting to improve a process that has too much variation often makes the process slower or reduce the effect of any improvements.  

Developed in the 1950s as a means to survive and compete against the giants of the automotive sector, lean manufacturing helped Toyota evolve from a small-volume producer (with little capital) to become a high-volume manufacturer in a process-rich environment. Toyota achieved this by using developments such as total production maintenance (TPM), just-in-time (JIT), Kanban, value stream mapping and Kaizen events.1 A summary of some of the lean terminology is shown in Table 1.

Lean Manufacturing practice in a cGMP environment

One metre of self-adhesive labels produces one metre of label backing waste. This roughly translates into 104200 tons of waste generated from the self-adhesive label industry. From this, the importance of reducing waste is clearly evident.  

The Big 5 pharmaceutical companies are taking notice of the need to become more "green" (and, of course, comply with the legislation) — a statement on one of the company's websites claims that "internally, efforts have been made to ... use more environmentally friendly packaging options". But is reducing the amount of packaging included in a crate sufficient? The answer is no! 

Recent developments in labels — especially in the form of "disruptive techniques" such as label replacement — appear to be rendering the label obsolete and have the potential to aid compliance with the legislation. 

In 1994, the European Union (EU) issued the Packaging and Packaging Waste Directive 94/62/EC, covering all packaging placed on the market within the EU and all packaging waste — whether disposed of at industrial/commercial sites or from private homes — regardless of the material used. The directive seeks to harmonize national measures concerning the management of packaging and packaging waste to provide a high level of environmental protection and ensure the function of the internal market.  

In 2004, the EU introduced amendment 2004/12/EC, which further clarifies the definition of the term "packaging" laid down in Directive 94/62/EC. According to this amendment, all materials used for containing, protecting, handling, delivering and presenting any type of goods are considered packaging. As a result, apart from conventional packaging, labels hung directly on or attached to a product as well as sticky labels attached to a packaging item are themselves deemed "forms of packaging".  

The amendment also increases the targets regarding recycling of packaging waste, therefore making the directive even more environmentally friendly. While these EU targets apply across all member states, implementation is the responsibility of the individual countries.   

The packaging directive has been transposed into UK domestic law by two sets of regulations: the Packaging (Essential Requirements) Regulations 2003, which set out the requirements all items of packaging must meet before being placed on the UK market, and the Producer Responsibility Obligations (Packaging Waste) Regulations 2005, which set specific recycling and recovery targets.

These regulations place the onus on the packaging and labelling industry to reduce the amount of waste it creates, however it is increasingly evident that traditional labelling methods are falling short when it comes to compliance. 

Thermal transfer and inkjet printers have traditionally been the preferred choice for the production of variable print-and-apply data labels. Many significant downfalls have emerged that now have the potential to render these labelling technologies obsolete. First of all, these processes do not adhere to the above legislations as they generate considerable waste, from laminate manufacturing and label printing through to label application on packaging.  

Additionally, these technologies involve the use of paints, inks, acids or solvents, which have a negative impact on the environment since they are associated with harmful toxic emissions. Costs are increased since the 280000 tons of silicone paper used in labels equates to approximately €530 million/year in manufacturing costs and €210 million/year for its disposal.

  Envirowise, the UK government programme that helps businesses improve their profits through waste reduction, estimates that businesses could save on average as much as €1500/employee by reducing waste.

Since pharmaceutical regulations require an ever-increasing amount of readable information to appear on packaging, print and apply labels fall short because of the restricted printable area that is available.  

The label replacement vision for the packaging (and pharmaceutical packaging) industries is radical. It aids the sector to move towards green manufacturing processes, but also provides additional benefits such as anti-counterfeiting properties. 

So what exactly is label replacement? Label replacement consists of a process that features a laser-reactive coating that is applied onto the specific data marking area of the outer case while the packaging is being produced. The coating is applied by using the conventional printing process of the packaging manufacturer. On the final production line, a low energy CO

 laser 'writes' the required variable data onto the mark area causing a colour change reaction of the coating from white to black. 

The most significant benefit of this solution is that it provides tangible results in the prevention of environmental pollution. This is particularly obvious when considering that there is no longer label backing or ribbons to dispose of, meaning that reduced environmental waste is created. In addition, packaging departments no longer suffer the associated disposal cost burden. Label replacement technology is totally non-toxic and since it does not require any paints, inks, acids or solvents on the production line, it does not generate any harmful toxic emissions.  

An additional benefit of label replacement — especially relevant to pharmaceutical companies — is that as there is no actual label (the data is integral to the pack), so the label cannot be peeled off. According to the World Health Organization (WHO), a counterfeit medicine is "one which is deliberately and fraudulently mislabelled with respect to identity or source. Counterfeiting can apply to both branded and generic products, and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient ingredients or with fake packaging."

  By using label replacement technology, counterfeiters are presented with an additional barrier, making it harder for the pharmaceutical product to be faked.  

It will remain to be seen whether pharmaceutical companies will commit lock, stock and barrel to being green, but by employing more environmentally friendly products and processes, such as label replacement, companies are taking another step toward this commitment. Of course, by employing a technique that adds extra benefits such as cost-effectiveness and counterfeit prevention, companies face a win-win situation.  

www.dti.gov.uk/innovation/sustainability/packaging/page29072.html

It will remain to be seen whether pharmaceutical companies will commit lock, stock and barrel to being green.

Pharmaceutical Technology Europe-10-01-2006

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