Water interacts with pharmaceutical solids at virtually all stages of manufacture, from synthesis of raw materials to the storage of the final dosage form. The interactions of water with powders is, therefore, a major factor in the formulation, processing and product performance of solid pharmaceutical dosage forms.  

The amount of water associated with a solid at a particular relative humidity (RH) and temperature depends on its chemical affinity for the solid and the number of available sites of interaction, the surface area and the nature of material.

  The physicochemical properties of pharmaceutical solids (such as flow, compaction, hardness and dissolution rate) are dependent on the presence of moisture, and several reports have been made in the literature to this effect.

Because of the importance of polymers in tablet and sustained-release matrices, the influence of storage conditions on the mechanical properties of tablets will be discussed separately. Compaction of powders into coherent specimens requires the formation of interparticulate attractions between the particles during the compression phase.  

However, after ejection of the tablet from the die, the tablet strength can change.

  This means that interparticulate attractions are also formed or disturbed during the postcompaction storage phase. Three main mechanistic explanations for the formation of interparticulate attractions have been proposed: 					

Rearrangement of solid material at the particle surfaces within the tablet.

Continuing deformation of particles in the compact after compaction.

Crystallization of dissolved material between neighbouring particles because of the movement of water within the tablet.

The first of these mechanisms is one of the main reasons for the postcompaction changes in the tensile strength of tablets. The rearrangement in the second mechanism can lead to either the formation of solid bridges between particles or to an increase in the bonding surface area of intermolecular attraction forces.  

It seems that this restructuring of solid materials is mediated or facilitated by the presence of adsorbed water and that water can show this function — although the point has not been reached where the state and thickness of the adsorbed water vapour allows a true dissolution of the solid material. 

For example, the first mechanism was proposed as an explanation for the postcompaction increase in tensile strength of tablets compacted from fine particulates (20–40 μm) of two water-soluble materials, saccharose and sodium chloride.

There are several factors that can change the effect of storage conditions including RH on the tensile strength of tablets. These factors will be discussed in this article. 

For tablets of saccharose and sodium chloride, the tablet strength increased generally during the storage.

  Although saccharose and sodium chloride are both water-soluble, larger differences in tensile strength of saccharose tablets were observed in comparison with tablets of sodium chloride after storage for 1 week. 

 For water-insoluble excipients, such as tablets of calcium hydrogen phosphate dihydrate, the tablet strength did not vary with time or storage conditions.

				  Changes in tensile strengths of sodium chloride and saccharose could be correlated to the changes in surface area of tablets.

It has been shown that there is transport or movement of solid material within the tablet during the storage results in a rearrangement of the material such that new interparticulate attractions are formed. This seems to be facilitated by the uptake of water from the environment. It seems reasonable that the RH of the environment during storage of tablets affects both the rate and the amount of water uptake. Thus, both the rate and the total degree of movement of solid material and the subsequent formation of interparticulate attractions are related to the amount of sorbed water.  			

This was also verified by a study on the effect of precompression processing and storage conditions on compaction properties of sodium chloride, sucrose, calcium hydrogen phosphate dihydrate and acetylsalicylic acid, which showed that the tablet strength increased with the postcompaction storage time for both sodium chloride and sucrose (water-soluble materials) at intermediate and high RH. However, for water insoluble materials of calcium hydrogen phosphate and acetylsalicylic acid no change was observed (Table 1).

 Table 1 The effect of storage condition on the tablet strength of some pharmaceutical powders.*			

Furthermore, for sodium chloride tablets it has been shown that the increase in compact strength occurred at 0, 33 and 57% RH, mainly within the first 4 h of storage.

				  However, only a minor change, if any, in the postcompaction tablet strength was noticed when the tablets were stored at 0% RH (Table 1). Although there are various studies on the effect of RH on the mechanical properties of tablet during the storage,

  it is very difficult to predict the effect of RH on the hardness of tablets as it has a complex effect on the physical ageing of compressed tablets and the variation in hardness.

 investigated the effect of temperature and humidity on the hardness of sustained release diphenhydramine HCl matrices.

				  The obtained results are tabulated in Table 2, which shows that the plateau hardness is achieved much more quickly for the tablets stored at 40 °C/75% RH than for the tablets stored at 25 °C/60% RH, which could be attributed to a faster acquisition of equilibrium moisture content at high temperature and RH (e.g., 40 °C/75% RH). 

Table 2 Hardness values of diphenhydramine  HCl-kollidon tablets.*			

Most of the changes in the mechanical properties of tablets could be related to the deliquescent point of the salts. As the humidity increases (but remains below the critical deliquescent point), the hardness of the salts increases. At a particular humidity, hardness would probably change until the compact attains its equilibrium moisture content. Thereafter the hardness would remain constant.  

Above the critical deliquescent point, the hardness of the salts decreases considerably.

  In the case of polymer tablets, the effect of moisture is not as straightforward as salts. For example, Reir and Shangraw reported adverse effects on the strength of Avicel tablets upon storage under elevated humidity. They attributed this to the absorption of water into the Avicel tablets causing bond disruption and loss in tablet strength.

Initial moisture content of pharmaceutical powders is an important factor affecting physicomechanical properties of tablets.

 Some investigations suggest only a limited effect for the powder storage conditions before preparation of compacts on the postcompaction strength changes even for materials prone to crystallize readily when exposed to humid atmospheres.

  A possible explanation is that the particle surfaces might be activated during compression because of interparticulate friction. However, a major effect has been observed in some cases. For example, Nyqvist and Nicklasson compared the effects of inducing moisture into Avicel powder prior to compression with the storage of 'dry' Avicel tablets at elevated RHs.

  The former produced an increase in tablet strength while the latter treatment produced a marked decrease.  

Partial moisture loss is the main factor increasing the hardness of tablets because of recrystallization of water-soluble excipients or a water-soluble drug in the void spaces on compression. 

The extent of the increase in hardness depends on the specific combination of drug and excipient and their physical properties (such as aqueous solubility, crystallinity and hygroscopicity), as well as the tabletting method.

  Therefore, recrystallization could be avoided by careful selection of excipients. Tablets prepared by direct compression are more susceptible to changes caused by humidity than tablets prepared by wet granulation. The changes in tablet behaviour upon ageing can be correlated with the moisture content of granules in tablets made by wet granulation. 

For tablets made by direct compression, it has been shown that those with high initial moisture content increase in hardness upon storage, with the magnitude of such increases being dependent upon the physical properties of the base and the absolute moisture content.

				  Among the tablets studied, lactose-based tablets with different initial moisture contents were found to be the most resistant to changes upon storage.

Effect of storage conditions on mechanical properties 

The effects of RH on the mechanical properties of hydroxypropyl methyl cellulose (HPMC) polymers have been extensively studied.

  It has been shown that the tensile strength of tablets obtained from HPMC powders equilibrated at 0% RH and then stored at different RHs before testing showed an initial plateau at about 5% wt moisture content and then a decrease that should be related to weakening of the interparticle bonds because of the softening of the HPMC polymers.  

But when HPMC powders compressed at the same compression force after equilibration at different RHs were stored at the same RH, the tensile strength of the tablets showed the plateau at 10% wt moisture content and then decreased. 

The effect of moisture content on a polymer's compaction properties has been reviewed briefly.

				  The presence of moisture in varying quantities could both increase or reduce the mechanical strengths depending on the formulation content.

explained the increase/decrease in tensile strength with moisture according to the type of moisture associated with polymers (Table 3).

Table 3 The effect of the type of moisture on the tensile strength and elastic recovery of HPMC K4M tablets stored at various relative humidities.*							

An increase in RH from 23% to 75% caused 7.5-,4.8-,and 2.3-fold increases in internally absorbed water, externally adsorbed water, and monolayer-adsorbed water, respectively. Similarly, the tensile strengths of HPMC K4M tablets concomitantly increased.  

The distribution of moisture in a material; the range and magnitude of the van der Waals' forces between the particles; and the development of additional bonds by plastic deformation and/or melting of powder particles should control the tensile strength of the tablets. Water molecules initially adsorbed on the surfaces may form a monomolecular layer and increase the van der Waals forces, thereby smoothing out the surface microirregularities and reducing interparticle separation.

  This monolayer-bound water can be regarded as part of the particles' surface molecular structure.

				  These effects would increase the tensile strength of HPMC K4M tablets with increasing moisture content. As more water molecules adhere to the surface, moisture may transfer into the material.

  This effect may soften the particles' surfaces; under high pressure, the area of contact between the particles will increase with plastic deformation and more solid bonds may form.

  These effects could account for the tablets' increased tensile strength. 

It has been suggested that water adsorption reduced tablet tensile strength because of condensation and multilayer adsorption.

				  The extent of multilayer adsorption in Table 3 can be estimated by subtracting the monolayer adsorption from the externally adsorbed moisture values. Although the amount of multilayer adsorption increased, tensile strength did not decrease. Therefore, the effect of moisture on tablet tensile strength is the result of the balance between the amount of monolayer-adsorbed moisture, internally absorbed moisture and externally adsorbed moisture.  

Maltodextrines have been extensively studied as excipients.

  They display a completely different type of profile compared with emcompress or Fast-Flo lactose, with significant decreases in crushing strength occurring from the time immediately after ejection until 1 day after ejection. Emcompress and Fast-Flo lactose are primarily brittle materials so the tablet porosity would not be expected to change much over time, whereas the plastically-deforming viscoelastic expands after ejection from the die. 

The maltodextrins had an initial rapid increase in tablet porosity, from the time immediately after ejection until 1 day after ejection, after which only small changes in porosity were seen. This initial change was probably a result of viscoelastic expansion of the material and can explain the large loss in crushing force that was seen. 

 The porosity changes observed after 1day were slight and not sufficient to explain how the consistent maltodextrin tablet-crushing force decreases with time. Bonds weakened within the tablet without concurrent changes in tablet size or other gross changes, such as increased tablet porosity.  

The influence of storage conditions on the disintegration time and dissolution rate

Following the administration of a drug through a solid dosage form, a sequence of steps is required before the drug reaches the systemic circulation. An orally administered solid dosage form undergoes disintegration and deaggregation, followed by the dissolution of the drug. The dissolved drug molecules must penetrate the gastrointestinal membrane and be picked up by the blood. Each of the steps involved may limit how fast the drug molecules reach the general circulation. Therefore, it is important to review the effect of storage conditions on the disintegration time of tablets and dissolution rate of drugs. 

Several studies have been reported on the changes in behaviour of disintegration of tablets upon storage.

Such changes were found to be responsible for some bioavailability problems.

  The water sorption and its effect on disintegration of tablets made of various excipients have shown that the physical properties of the tablets were influenced by water uptake or loss during storage. At low RHs, the disintegration times increased and at high RHs decreases were observed.

It has been shown that tablets prepared by direct compression were more susceptible to changes caused by humidity than tablets prepared by wet-granulation.

  There are many studies that examine the effect of ageing on tablet disintegration. Large differences are apparent among different formulations and tabletting methods.

 The changes in tablet behaviour upon ageing were correlated with the moisture content of granules in tablets made by wet granulation. Tablets made from granules with high initial moisture content(4%), on storage, showed increases in hardness induced by partial loss of moisture.

It has been shown that tablets made from granules with low-moisture content (2%) gained hardness during storage as a consequence of the partial loss of moisture. Such increases in hardness, which were not related to initial tablet hardness, showed minimum effect on tablet disintegration.

 investigated the ageing of tablets prepared by direct compression of bases of different moisture contents.

  The storage-induced changes in disintegration were evaluated for tablets made by direct compression of three different bases with different initial moisture contents. 

The increases in hardness may increase the disintegration time. The tablets with low initial moisture content were minimally affected by storage.

  The gain of moisture by some of these tablets led to reduction of the disintegration times. Among the tablets studied, lactose-based tablets with different initial moisture content were found to be the most resistant to changes upon storage.  

In the development of tablets, it is generally recognized that ageing may cause chemical and physical changes that may modify the dissolution of drugs from compressed tablets. These changes in dissolution may alter the bioavailability of the active drug substance. 

Articles

Dosage Forms

Water interacts with pharmaceutical solids at virtually all stages of manufacture, from synthesis of raw materials to the storage of the final dosage form. The interactions of water with powders is, therefore, a major factor in the formulation, processing and product performance of solid pharmaceutical dosage forms.

The effect of storage conditions on the physical stability of tablets

Nanoparticulate drug carriers include a class of particles made of polymers or lipids that — because of their size and chemical composition

—permit systemic and local treatment.  

In general, these systems are expected to protect a drug from degradation, enhance drug absorption by facilitating diffusion through epithelium, modify the pharmacokinetic and drug tissue distribution profile and/or improve intracellular penetration and distribution.

They can be administered by all possible routes of administration, generally improving both bioavailability and therapeutic efficacy of the carried drug.

  They represent an alternative class of vehicles to liposomes to transport drugs straight to the targeted diseased cells in the body. 

Table 1 Definition of the different types of nanoparticulate drug carriers and schematic representations.4â18			

Numerous types of nanoparticle drug carriers have been developed (Table 1). The range of applications includes the treatment of all major public health diseases including severe infections and cancer. They are also strongly believed to potentially solve the problem of the 

 delivery of biomimetic molecules such as nucleic acids, proteins, peptides and very insoluble drugs, which is very difficult by other means (Table 2). 			

Although several liposomal formulations have been marketed since 1995 — illustrating that nanotechnology can be used to administer toxic drugs such as antifungal and anticancer agents — two new formulations for polymer nanoparticles entered clinical trials recently for cancer therapy. 

This article focuses on the development of nanoparticulate drug carriers, highlighting several of the key issues being addressed up to now. 

Table 2 Suggested nanoparticulate drug carriers as a function of the physicochemical characteristics of the drug to be administered.3â31 

The design of nanoparticulate drug carriers must fulfil the following requirements: 					

Composition must be acceptable for use in human therapy (biodegradable, biocompatible, nontoxic).

Size must be suitable for administration to humans by different routes and allow diffusion inside the body to reach the biological target site.

The biodistribution should suit the therapeutic target. 

The carrier must be loaded with the drug and should only release the drug in a controlled manner once the carrier has reached the biological target site.

As lipids are part of living constituents, they were considered to be suitable chemicals to formulate solid lipid nanoparticles (SLNs) and nanocapsules (LNCs) (Tables 1 and 2). 

Synthetic polymers offer an almost infinite array of chemical composition and structure combinations. However, only a few have the requirements that make them useful as nanoparticulate drug carriers.  

The prime candidates are polyesters including polylactide (PLA) derivatives and polyepsiloncaprolactone (PCL), polyalkylcyanoacrylate (PACA) and corresponding copolymers with polyethylene glycol (PEG), polysaccharides and polyethylenimine (Tables 1 and 2). 

Natural macromolecules including polysaccharides (chitosan, alginate, pectine) were introduced to formulate hydrogel nanoparticles. Research is continuing to find suitable new polymers because polymers can be produced at lower cost than lipids and should be more interesting (economically) based on economic considerations.

  Polyesters of polymalic acid, polyamino acids of polybenzyl-glutamate) and pH- or temperature-sensitive species are growing in popularity.

Whatever the material constituting the drug delivery device, the second requirement is to produce particles small enough to diffuse across biological barriers encountered in the body to transport the drug from the administration site down to the target tissue and/or cells. Considering the mucosal route, the smaller the nanoparticles, the better they can transport drugs across mucosa.

After intravenous administration, particles with a diameter less than 100 nm are generally less recognized by macrophages of the host defence system (macrophage of the mononuclear phagocyte

system [MPS]) and can circulate for several hours in the blood stream. Their small size also promotes their diffusion through fenestration of the altered blood vessels found in diseased tissues.

The various methods developed to prepare nanoparticulate drug carriers have been reviewed in several papers.

  The principle of the methods depends on the type of particles to produce, the raw material and the drug to be encapsulated. The diameter of the particles produced is generally below a few hundred nanometers. 

The methods are reproducible and most of them can easily be scaled up to be industrialized (i.e., nanoprecipitation producing nanocapsules, anionic emulsion polymerization producing PACA nanoparticles, production of SLNs). Continuous processes also exist to produce nanoparticles by nanoprecipitation and SLNs.

  Emerging methods include environmental-friendly procedures based on the self-assemblage of macromolecules in aqueous solutions, gelation of hydrophilic gelling polymers, formation of lipid nanoparticles and nanocapsules, emulsion polymerization of pure monomers in a water continuous phase and methods using supercritical fluid carbon dioxide as the solvent.

Reaching the ultimate goal of drug targeting requires that the fate of the nanoparticulate drug carrier will be perfectly controlled 

. This requires a specific design of the particle. As previously discussed, particle size is one parameter to consider. 

Apart from the size criteria, the biodistribution of particles is greatly influenced by the interactions occurring between body components and the nanoparticle surface. Thus, another important factor includes the composition of the nanoparticle surface. For instance, coating nanoparticles with PEG reduces the opsonization on their surface hence the uptake by the MPS after intravenous

Thus, PEG-coated nanoparticles (i.e., 'Stealth' nanoparticles) remain in the blood for several hours while their uncoated counterparts accumulate in the MPS within a few minutes following administration. Recently, it was shown that the conformation of chains of macromolecules grafted on the nanoparticle surface also influences the interaction with blood components.

  Thus, depending on the coating material and conformation, it is now possible to suggest several general rules to design nanoparticles that deliver drugs either to macrophages of the MPS or outside the MPS area.

  Nanoparticles escaping the MPS uptake can be used to retain drugs in the blood compartment or to distribute therapeutic compounds in tumoural or inflamed tissues thanks to the local enhanced permeation retention effect occurring in diseased tissues.

  The specificity of recognition of the target cells by the nanocarriers requires a subsequent sophistication of labelling address, which must be attached on the nanoparticle surface too.

				  Convincing results of targeting were obtained by coupling monosaccharides or folate residues on the nanoparticulate drug carrier surfaces.

  Other strategies are based on the covalent attachment of the biotin-binding protein, NeutrAvidin, enabling the binding of biotinylated drug-targeting ligands such as antibodies by avidin–biotin complex formation.

				  More recently, specific nucleic acids named aptamers were considered for targeted delivery and uptake of nanoparticles in a cell-specific manner.

It can be expected that the extension of the targeting strategy will progress further with new data from the biologists identifying possible specific target receptors on cell surfaces and corresponding ligands, and from progress in molecular imprinting techniques.

For oral or nasal administration, the use of chitosan as a coating material of the nanocarrier surfaces may promote the bioadhesive properties of the drug delivery device on the mucosa, hence promoting absorption of drugs by the epithelium.

Many methods of nanoparticle preparation were developed because it is quite a challenge to incorporate a drug into a nanocarrier (Table 2). Most lipophilic small molecules (such as indomethacin, amphotericin B, paclitaxel) could be encapsulated into PLA, PLGA and PCL nanoparticles, in SLNs, in LNCs and in polymer micelles. 

Macromolecular drugs including therapeutic peptides and nucleic acids were successfully encapsulated in nanogels. Nucleic acids can be incorporated in nanocarriers by forming polyelectrolyte complexes with polycations such as polyethylene imine and chitosan.  

Nanoparticles made of PACA accept various types of drugs because of the wide variety of systems being produced with this polymer. Small molecules were encapsulated in nanospheres whether they were hydrophilic (ampicillin, doxorubicin) or poorly soluble (saquinavir, paclitaxel). Peptides including insulin and human growth hormone were encapsulated in oil-containing nanocapsules and in nanospheres, respectively, whereas nucleic acids were encapsulated in water-containing nanocapsules.  

The encapsulated or entrapped drug should be released from the carrier only when it will reach the biological target.

 Indeed, the main difficulty is to keep the drug inside such small carriers because of the enormous exchange surface with the surrounding external media. Thus, the release of the drug often occurs as a burst as soon as the drug-loaded nanocarrier is transferred in a releasing media. 

This phenomenon can be reduced bycomplexing the drug with components of the carriers

  or by forming a hydrogel barrier at the carrier surface.

  Temperature- and pH-sensitive systems are another option to provide drug release on demand.

  Molecular imprinting techniques may soon provide interesting matrices that are able to retain drugs inside the nanospheres, eventually triggering the release using an external stimulus.

Nanoparticulate drug carriers represent a platform to deliver numerous drugs used in the treatment of major health threats such as cancers, infections (i.e., HIV, malaria, tuberculosis), metabolic diseases (such as diabetes and osteoporosis) and autoimmune diseases (glaucoma, for example). Different routes of administration may be used (Table 3). Other potential therapeutic applications concern the management of graft rejection, inflammation and pain.

Table 3 Mode of administration of nanoparticulate drug carriers and therapeutic applications.3 			

Each case represents a huge number of patients and an enormous potential market. Nanoparticulate drug carriers offer the opportunity to overcome many of the delivery problems encountered with old and new therapeutic compounds.  

Nanoparticulate drug carriers will be important for the administration of molecules that have high therapeutic potential, but currently produce severe side-effects. Because nanotechnologies allow a more precise delivery of the therapeutic compound to the target cells, they may also reduce drug concentrations in healthy organs and tissues. The improvement of drug delivery minimizing the side-effects has been proved in treatment of cancer with doxorubicin and of infections with amphothericin B or halofantrine.

The use of nanoparticulate drug carriers can also help to solve the problems of drugs coming out from the discovery pipelines, which often present special delivery challenges. Many of them are poorly soluble compounds, which results in limited bioavailability with low and/or erratic absorption when using traditional pharmaceutical formulations. 

This is, for example, the case of paclitaxel, a lead molecule in cancer therapy. Nanoparticulate formulations of paclitaxel have avoided the use of the excipient Cremophor (responsible for severe side-effects), which considerably limited the conventional treatment.

  Interesting results were also obtained considering the oral administration of nanoparticulate formulations of poorly soluble compounds (paclitaxel, saquinavir).

Drug Delivery

Nanoparticulate drug carriers include a class of particles made of polymers or lipids that - because of their size and chemical composition -permit systemic and local treatment.

Developing nanoparticle drug carriers

In the pharmaceutical industry, microbiological culture media play a key role in signalling the presence or absence of microorganisms at any stage of production. For this reason, the validation requirements of the European, United States and Japanese Pharmacopoeias in respect of such media will need no introduction to readers of this publication. Perhaps less well known, however, are the quality criteria that distinguish the many different suppliers of culture media — criteria that can help pharmaceutical contractors provide further reassurance of their own quality systems to their end customer. 

The production, quality assurance and post-sales support of culture media make it a demanding and multifaceted business. Because conclusions drawn from the use of these products have a direct impact on quality standards in pharmaceuticals production (and ultimately, on patients' lives) it is hardly surprising that the achievement of excellence in culture media manufacture calls for the highest levels of expertise and control. 

In the pharmaceutical industry (just as in clinical diagnostics, food and water testing applications), there is an implicit requirement that microbiological culture media should perform consistently to an agreed specification. This can only be achieved through rigorous application of quality management throughout the manufacturing process. For many years, the quality standard towards which culture media manufacturers in Europe have worked has been BS EN ISO 9001:2000. So, it might have appeared safe to assume that BS EN ISO 9001:2000 registration should be the first key criterion for selecting a culture media supplier. 

However, while BS EN ISO 9001:2000 registration signifies compliance with defined quality management standards on a cross-industry basis, there is another more specific standard — ISO 13485:2003 that applies even more closely to culture media manufacture. 

This standard is based on the BS EN ISO 9001:2000 quality management standard, but it is oriented specifically towards the design, development, production and installation of medical devices and related services. Closer scrutiny of the requirements of ISO 13485:2003 reveals its relevance to the exacting standards of the pharmaceutical industry. It is a process standard (as opposed to a product standard), which not only encompasses the operation of a quality management system, but also focuses on meeting customer expectations and, crucially, compliance with regulatory requirements. 

Whenever BS EN ISO 9001:2000 requires a supplier to document a procedure, it also calls for the implementation and maintenance of that procedure. ISO 13485:2003 goes further by extending the 'document, implement and maintain' requirement to include the meeting of specific customer/industry needs. In addition, it places greater emphasis on using procedures to control and regulate the way in which specific processes and activities should be performed. This gives culture media purchased from ISO 13485:2003 registered suppliers a clear competitive edge. 

However, ISO registration is not the only external assessment criterion against which a potential supplier can be evaluated. Culture media suppliers that are audited by FDA can be identified on the agency's website (

Your chosen supplier should also be able to demonstrate a proactive stance in keeping up-to-date on changes in legislation and regulatory requirements. Ensure that your audit questions this area — does the manufacturer have staff dedicated to this activity?   

Having short-listed a potential supplier on the basis of its ISO and/or FDA registration, the next step is to make your own enquiries into the nature of its quality systems. Normally, the vehicle for such enquiries would be an audit, conducted either in the form of a written questionnaire or a site visit. 

Often, written questionnaires follow a standard format based on criteria specific to pharmaceuticals manufacture. It should be borne in mind, however, that key criteria for culture media selection are somewhat different to those that would typically apply to pharmaceuticals. In practice, site visits may yield more meaningful information than questionnaires when selecting a culture media supplier. It is helpful in this context if those involved in the audit from the contractor's side have been able to gain a broad understanding of the processes involved in manufacturing culture media. It is essential that the potential supplier should be able to demonstrate in-depth understanding of the requirements of pharmaceuticals production. 

Additional questions about the supplier's quality systems include: 					

What documentation and certification is provided with regard to the origin of raw materials?

What information is provided regarding the product performance and shelf life?

What quality control procedures are in place?

It is vital to assess their knowledge of standards and guidelines that affect the pharmaceuticals industry and indeed their ability to monitor the introduction of relevant, new regulations as and when they arise. 

Face-to-face assessments will yield much more information than tick box responses to standard questions. Plus, they provide an invaluable feel for the supplier's organization, in terms of its overall competence and ability to provide ongoing support to its customers. 

This is an important, yet seemingly intangible aspect of culture media selection. Those who make procurement decisions are seldom the same individuals who will have to prepare and work with the media on the laboratory bench. Laboratory technicians may, from time to time, need advice on aspects of media performance or storage. Availability of technical support to product end-users is an essential resource for ensuring that media are prepared, stored and utilized correctly. In this context, the concept of quality should not only apply to the manufacture of the media — it should also continue throughout the product's lifetime of usage. 

Other aspects of a supplier's customer service should also be taken into consideration, such as the efficiency of their sales and order processing operations: 					

Is there a business management system in place to give instant visibility of stock availability? 

Are there dedicated staff with whom you can coordinate all purchases through a single point of contact? 

Can the supplier respond quickly to urgent orders? 

Is it possible to reserve stock within a single batch? 

Is there an experienced support team available to answer questions on all technical aspects of culture media?

Although these issues may at first seem less important than product quality, they are factors that can greatly benefit you as the product user, and help to offer reassurance to your customers. 

Product quality and performance will, nevertheless, remain the primary focus of any supplier assessment audit, requiring detailed investigation into the scope and efficacy of the manufacturer's quality systems. While the primary responsibility for quality lies with the manufacturer of microbiological culture media, regulatory requirements dictate that consumers must also perform tests on incoming products for validation purposes. By selecting suppliers that are fully conversant with the requirements of the pharmaceutical industry, it is possible to benefit from potentially time and money saving synergy in regard to their quality and your required validation. 

The level of detail in the quality documentation that a manufacturer issues to accompany its products should be a key factor in supplier selection. For example, product specifications should provide all the relevant details, such as typical formulation, test and pass criteria against which product performance is assessed, and with which standards these performance tests comply. Quality control certificates giving batch-specific information and quantitative test results are considered advantageous, and are readily available with each consignment or electronically. Other documents demanded by pharmaceutical companies include certificates of origin, which provide the appropriate reassurance in relation to the source of material of ruminant origins in a given product. 

Your audit might also ask if your chosen supplier provides culture media to other industry sectors such as food microbiology and for clinical applications. If so, its products will also be subject to particularly stringent systems of testing that utilize methods and reference organisms relevant to all these different end-use areas — thus enhancing confidence in their performance. 

It is the combination of the quality issues addressed here, and the culture media manufacturers' in-depth appreciation of the requirements and working practices of the pharmaceutical industry that will set the very best of the suppliers apart from the rest.  

is the quality assurance manager at Oxoid Ltd (UK). 

Outsourcing

The concept of quality should not only apply to the manufacture of the media - it should also continue throughout the product's lifetime of usage.

Ensuring a culture of quality

Biotechnology companies face some interesting technical and regulatory challenges in 2007, and beyond, in the race to bring patients a wide range of innovative products. According to a recent study from the Tufts Center for the Study of Drug Development (CSDD), the average cost of developing a new biopharmaceutical drug is around $1.2 billion. And biotech products take almost 98 months, on average, to get through clinical development and regulatory review — about 8% longer than for traditional molecule therapeutics. Therefore, there is mounting pressure on manufacturers to cut costs and speed up the production cycle.  

On the plus side, the CSDD report states that biologics have a higher clinical approval rate than conventional pharmaceuticals — 30.2%, compared with 21.5%. There are currently several hundred biotech-based drugs in clinical trials, representing around a quarter of all drugs in development — a proportion that looks set to increase.  

Besides recombinant proteins and monoclonal antibodies, there are now cell and tissue therapies, DNA vaccines, and RNAi-based products requiring GMP manufacture in clinical trial quantities. There is also increasing interest in the development of biosimilar products, following the EMEA's eventual approval of Sandoz's Omnitrop (a 'follow-on' version of recombinant human growth hormone) and Biopartners' Valtropin, a recombinant somatropin in 2006. An increasing number of biotech drugs come off patent in the next few years, so manufacturers must start thinking about producing biosimilars now.  

A couple of years ago, the prospect of this heavy and diverse 'workload' precipitated panic within the industry over cell culture capacity. Was there enough fermentation capacity to produce the hundreds of kilograms of product to serve clinical trial and commercial demand?  

The capacity crisis never really materialized, according to Avinoam Kadouri, chairman of the European Animal Cell Technology Industrial Platform. Today, the emphasis has shifted towards smarter upstream and downstream technologies, which can decrease both cost of goods and manufacturing times. "Required fermenter size will shrink, as high producing clones and cheap, simple media are developed," he predicts. "And more investment in downstream processing will mean greater recovery of product." 

For example, there is increasing emphasis upon selecting high-producing clones using technologies such as Cyntellect's LEAP (laser enabled analysis and processing), marketed by SAFC Biosciences, which allows rapid screening of millions of cells for the rare high protein producers. In the downstream area, Pall's Process Proteomics uses a microarray-based approach to optimize chromatography conditions for purification in hours, rather than the days that would be required by conventional column experiments. Such technical developments, while not yet universally adopted, can help companies achieve their goals of reducing costs and timelines.  

Manufacturers will also have to deal with the increasing shift away from bovine serum and other animal component-containing media, replacing these with synthetic media that give equivalent — or even higher — productivity in cell culture. Regulatory authorities now require companies to justify any continuing use of animal components in production processes. Companies also need to consider whether to replace some, or even all, of their stainless steel plant with plastic disposable components. Disposables score on flexibility and save on cleaning and sterilization costs, but can be a costly investment.  

Of course, the availability of manufacturing capacity is still important — whether it is based upon stainless steel or disposables — especially for academic groups and small biotechs trying to produce sufficient of their therapeutic to GMP standard to progress to proof of principle.  

There is no shortage of contract manufacturing organizations, both in Europe and, increasingly, in the Far East and India — should a company decide to outsource. And this month (January 2007) sees the opening of the UK's National Biomanufacturing Centre in Liverpool, which will help academic groups and SMEs get a foot on the manufacturing ladder. There is also a £3 million access fund, which allows for purchase of development and clinical manufacturing services at the Centre.  

Small companies need other help too and this should be forthcoming from the EMEA's new SME office, which will offer a range of incentives, including fee reductions for scientific advice and inspections and deferral of fees for an application for a marketing authorization. And on 1 January 2007, the EU introduced new state aid rules that allow Member States to provide tax breaks and other help to young innovative companies (YICs), such as small biotechs, without breaking European competition rules (at the time of publishing, it was anticipated that the EU would introduce these new state rules). The YIC status was first introduced in France and Belgium and EuropaBio has been campaigning for it to be widened to the whole of Europe for some time, according to Dr Andrea Rappagliosi, chairman of its healthcare council. 

Another top priority for EuropaBio this year is the implementation of the EU's Regulation on Advanced Therapies, which is to cover gene, cell and tissue-based therapies already on the market, or coming onto the market in the future. "This will provide a centralized European platform for regulation for the new therapies that will be developed over the next 5–10 years," says Dr Rappagliosi. The regulation will cover manufacturing and technology issues, such as risk management and traceability, although decisions on the use or nonuse of stem cells, including those from embryonic sources, will remain the responsibility of Member States. It will also include a mandatory centralized procedure for obtaining marketing approval through EMEA, and it is hoped this will support companies in developing cell and tissue therapies. 

EMEA is also developing guidelines on clinical and non-clinical aspects of biosimilar medicinal products containing a biotech-derived protein as an active substance. This is an important opportunity for companies to place greater emphasis upon process analytical technology to show to the regulatory authorities that their 'generic' version of a recombinant protein is safe, pure and effective in comparison with the original product.  

As far as the biotech business scene is concerned, Dr Kadouri predicts more competition — with a further increase in the number of companies. All the big pharmas are interested in biotech now, so watch for more developments, such as AstraZeneca's acquisition of Cambridge Antibody Technology, Novartis' purchase of NeuTec Pharma and, on the other side of the pond, Merck's acquisition of RNAi company Sirna. "In the last few years, biotechs have participated in lots of deals — collaborations, licensing, codevelopment, spin-offs and acquisitions," says Dr Rappagliosi. "These deals can only benefit biotech by helping build a critical mass and it is an integral part of how the industry is evolving. We are expecting many more such deals in 2007." 

Biopharmaceuticals

There are currently several hundred biotech-based drugs in clinical trials, representing around a quarter of all drugs in development - a proportion that looks set to increase.

A New Year for biotech

Traditionally, pharmaceutical manufacturing has been accomplished using batch processing with quality control testing conducted on samples of the finished product. This conventional approach has been successful in providing quality pharmaceuticals to the public for a number of years. Significant opportunities, however, exist for improving pharmaceutical development, manufacturing and quality assurance (QA) through innovation in product and process development, process analysis and process control.

  Other sectors, for example, manufacturing and chemical, have already adopted new ways of thinking. The pharmaceutical industry, through a number of regulatory initiatives, is now beginning to develop these concepts. 

Since 2004, FDA, recognizing the need to promote a greater scientific approach to pharmaceutical development, has instigated new initiatives such as 

Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach 

 Guidance for Industry Process Analytical Technology (PAT) — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.

 In these documents, there is an emphasis on using new scientific understanding and innovative technologies to provide a science-based approach to pharmaceutical development. More focused and scientifically justified strategies will enable the pharmaceutical manufacturer to build quality into products rather than assure quality through testing to poorly defined specifications. The principles of quality by design (QbD) should be applied to generate process understanding, which must be underpinned by using multivariant models describing processes and their associated causes of variability. 

There are many tools recommended within the PAT framework that enable process understanding for scientific, risk-managed pharmaceutical development, manufacture and QA.

 These include multivariant tools for experimental design, data acquisition and analysis, process analysers (in-/on-/at-line) for the real-time monitoring of product quality, process control systems and knowledge management software applications. Much of the innovative thinking with respect to PAT and QbD is, however, focused on the development of novel probes/sensors for real-time and in-line monitoring of manufacturing processes. 

This philosophy must be coupled with a greater understanding of the risks and causes of variability in pharmaceutical dosage form manufacture to achieve desired product quality and optimal clinical performance.  

Traditionally, tools for multivariant data analysis, such as principal components analysis (PCA) and partial least squares projections to latent structures (PLS), have been used in conjunction with design of experiments (DoE) to investigate the underlying relationships in pharmaceutical processes.

  New knowledge engineering technologies based on artificial intelligence (AI) have, however, in recent times been developed that offer some advantages compared with conventional multivariant tools and can be used to compliment existing technology.

This article aims to highlight the value of using AI technology to understand complex multivariant systems such as pharmaceutical formulations and processes. Used appropriately, these tools enable the identification and evaluation of product and process variables that may be critical to product quality and performance, and allow the generation of predictive models that link changes in important/critical variables to changes in key product quality attributes — and ultimately clinical quality and performance. 

"Perhaps we don't hear much about AI methods used within today's technologies because it's slightly unnerving when computers emulate human thinking. Yet we, and computers themselves, continue to improve the way AI works quietly in the background to optimize, reduce process costs, and improve timing and product quality. For some tough, nonlinear applications, AI may be the only solution."

In recent years, AI has become important in a number of fields in helping to make better use of information, increasing efficiency and enhancing productivity. Many UK banks have used AI technologies to detect fraudulent behaviour by analysing transactions and alerting staff to suspicious activity. This has reduced fraud cases for the first time in nearly a decade by more than 5% to £402.4 million in 2004.

  In bioinformatics, AI has been used to manage, discover and interpret information/knowledge from biological sequences and structures. In the manufacturing industry, AI is used to achieve automotive control of production processes. 

AI is defined as the ability of a machine to learn and "think" for itself from experience and perform tasks normally attributed to human intelligence; for example, problem solving, reasoning and process understanding. AI technologies are widely used in situations where tasks are multidimensional, and where relationships are nonlinear and extremely complex; for example, the underlying relationships between formulation ingredients, process conditions and drug product quality.  

A number of AI technologies have been developed and are available as commercial software applications, including neural networks, neurofuzzy logic and genetic algorithms (GAs). Artificial neural networks (ANNs) are computer-based programs designed to mimic the process of the human brain's cognitive learning. ANNs work by building up a network of interconnecting processing units or nodes, which are the artificial equivalents of biological neurones. The ANN is able to discover knowledge (e.g., cause–effect relationships) that is hidden in experimental data and generate predictive models linking important factors to key measurable outputs; for example the effect of drug particle size and wet granulation conditions on tablet dissolution. 

 is a powerful problem-solving technique based on the mathematical theory of fuzzy sets first defined in 1960s by Zadeh.

In recent years, AI has become important in a number of fields in helping to make better use of information, increasing efficiency and enhancing productivity.

Pharmaceutical Technology Europe-01-01-2007

The effect of storage conditions on the physical stability of tablets

Developing nanoparticle drug carriers

Ensuring a culture of quality

A New Year for biotech

Artificial intelligence the key to process understanding

Industry consults on new regulations