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A meeting, sponsored by Vifor, explored peculiarities of nano-scale substances, and discussed nanomedicines to address not only the regulatory environment but also how responsibilities are challenged
Roderick Beard BPharm MSc MBA MProf MRPharmS
Sunderland Royal Hospital, UK
Gerrit Borchard PhD
School of Pharmaceutical Sciences
Nanotechnology has an increasing importance for the preparation of therapeutics, the implications of which have not been assessed sufficiently. Other than for biologics, no clear regulatory pathway, based on scientific knowledge, for the marketing authorisation of such ‘nanomedicines’ exists today. In addition, no regulatory strategy for the assessment of follow-on products of nanomedicines – ‘nanosimilars’ – and their substitutability has been established.
The term ‘nano’ is derived from the Latin ‘nanus’ (meaning dwarf). In the SI system, it signifies a factor of 10–9. Nanotechnology is essentially the manipulation of properties of materials and devices at the very small – molecular to atomic – scale. Nanomedicine, in turn, denotes the development of drug formulations that have properties (for example, particle size, surface charge) at the nanoscale, which will determine their bioactivity and safety by affecting ADME. Formulations, such as liposomes (Doxil®), nanoparticles, such as iron carbohydrate particles (Venofer®) and albumin nanoparticles (Abraxane®), but also polypeptide mixtures (Copaxone®), are representatives of such nanomedicines that have already been introduced into the market. Marketing authorisation, however, was granted in the absence of in-depth knowledge of important quality, toxicological and clinical parameters, and in the absence of a dedicated regulatory strategy.
This roundtable of experts in the field of nanomedicine convened to discuss these aspects and the influence on hospitals pharmacists’ responsibilities. The major conclusions are summarised here.
Challenges: characterisation of differences
In contrast to traditional drug formulations, the active pharmaceutical principle (API) and the formulation or ‘carrier’ in nanomedicines form a single entity. The properties of this entity are key for their pharmacokinetic profile, efficacy and toxicity. A small change in the composition or the physico-chemical properties of such nanomedicines, for example, caused by a change in the manufacturing process, may entail severe clinical performance changes.
The challenge in the characterisation of nanomedicines today is to determine which properties do indeed have an influence on the clinical performance and to define specifications for these properties. One area that will definitely play a role is the interaction of particulates with the immune system. Virtually any particle, no matter of which material, will raise an immune reaction, stimulated by the particle surface, that is, ‘what the immune system sees’. In this regard, one must consider that with decreasing size, the ratio of material comprising the particle surface to bulk material is increasing. For example, a particle of approximately 30nm will have 5% of its mass as part of the surface, a 10nm particle will have 20% of its mass as surface area, and a 3nm particle will have 50% of its mass as surface area. The smaller the size, the more important the surface properties become with respect to activity and safety of nanomedicines.
Within a given batch of a nanomedicine, surface heterogeneity will certainly occur – because ‘no two particles are the same’. This ‘microheterogeneity’ – to use a term from the biosimilars discussion – is of relevance, not at least for the pharmacokinetic profile of the nanomedicine (see below). One challenge, however, is to accurately define, as for biologics, the extent of heterogeneity to be allowed for, and to define which parameters to use for the prediction of clinical outcome.
The second challenge lies in our yet limited ability to characterise such nanomedicines. Today, we do not have sufficient analytical means to be able to discern small differences between particles. The two options to cope with this situation are to either deduce from clinical effects observed during treatment, or to further adapt or newly develop techniques to better determine differences in, for example, composition and charge of particle surface and shape. As for biologics, the characterisation of nanomedicines demands a multi-pronged approach, as not one method can supply sufficient information. Some techniques used in the characterisation of biologics may even be suitable and adapted to the characterisation of nanomedicines. However, these techniques require standardisation and inter-laboratory validation. Even then, due to the batch-to-batch heterogeneity of nanomedicines, inconclusive results may be obtained. As an example, five different batches of Doxil gave five different biological responses in a cell-based assay.
Current methods of measuring the size of nanoparticles can supply data that are variable and may be prone to interpretation. Unless consistent methods of characterisation of the particles are found, it is difficult to guarantee the efficacy and safety, let alone predict ‘similarity’ of two products.
It has to be borme in mind that these complex nano-particular compounds consist of non-homomolecular structures not to be fully characterised but with potential clinical impact when small differences occur.
The particle size can be made consistent within a certain size range, which described by the polydispersity index (PI). A PI between 0.1 and 0.2 may be applied as a pharmacopoeial requirement; however, it may be very different once the particles are introduced into the body, for example, through aggregation. In addition, the PI does not inform which proportion of the batch is in which size range.
As mentioned, surface characteristics may not be homogenous in a given batch, or between batches. If the surface properties of particles vary, the pharmacokinetics may vary, and therefore the proportion of drug at the target site may differ. This influence was shown, for example, for Doxil (liposomal doxorubicin), which is eliminated through ‘opsonisation’, that is, the coating with plasma proteins and immune recognition. Differences in surface, or even different surface curvatures, may lead to a different coating with plasma proteins, and thus to variations in elimination profiles. The elimination profile of Doxil was shown to be biphasic, indicating the presence of different species of liposomes. These differences will change the concentration at the target site as well as at toxicologically relevant tissues (‘nano side effects’).
It is agreed that bioequivalence of two products should be defined through the concentration of API at the target site (for example, tumour) and not expressed in terms of plasma concentrations. Nanoparticulate preparations in cancer treatment, such as abraxane, rely on the passive targeting relayed by the so-called enhanced permeation and retention (EPR) effect.
Particles, rendered ‘invisible’ or ‘stealth’ to the immune system by coating with polyethylene glycol (PEG) by a process termed PEGylation, remain longer in the systemic circulation after injection. Due to this, PEGylated particles may extravasate through the leaky vasculature in tumour tissue (enhanced penetration), increasing API concentration locally while reducing side effects at off-target tissues. Cancer tissue is absent of lymphatic drainage, thus particles are not eliminated from the tumour (enhanced retention). What then is important for efficacy is the bioavailability of the drug at the target site, that is, the drug released from the carrier and diffusing into the cancer cells.
Today we know that the extent of the EPR effect varies not only with the type of tumour (for example, different composition of the extracellular matrix, vasculature leakiness), but also with the nanoparticle properties such as extent and fashion of drug loading, size and size distribution.
To complicate matters further, problems can arise from a patient’s previous exposure to sub-parts of the nanoparticle, for example, polyethylene glycol. PEG is used extensively in the food industry, which could affect its use as a nanocarrier, as the immune system might recognise the drug and render it ineffective by releasing neutralising antibodies. Twenty-five per cent of the population have already been shown to have antibodies to PEG caused by exposure to the polymer in food. How would a clinician deal with such potential problems when exposure could be a relatively common occurrence?
All complex drug formulations such as nanomedicines may show different effects and pharmacokinetic profiles for different patient groups, for example, pregnant women, infants, or the elderly, and may be dependent on the stage of the disease. How do formulations have to look to be efficient and safe in these subgroups? In general, these challenges were neither anticipated nor considered when we started out designing these carriers more than 20 years ago, and thus were not included in the development of nanomedicines and their follow-on versions currently on the market.
Preparation of nanomedicines may be achieved in a reproducible fashion for key parameters at the lab scale; however, this becomes difficult during scale up from 1ml volumes to clinical batches. As is the case for biologics, it is assumed that for nanomedicines the rule that ‘the process is the product’ applies. Differences may be introduced during manufacturing by small changes in production parameters and will lead to different ADME and efficacy profiles. Manufacturing of nanomedicines is generally difficult to control and relies on the establishment of in-process controls and specifications. For some nanomedicines on the market, such as Venofer, this was achieved, as the iron sucrose product shows very low batch-to-batch variability with respect to physicochemical data and from animal testing, and appropriate storage does not alter properties of the originator over time.
However, the manufacturing process and its controls and specifications remain proprietary to the manufacturer and can thus not be reproduced by a follow-on or ‘intended copy’ manufacturer. If it is therefore not possible to know if the manufacturing process of the follow-on product is consistent with the original product, how can it be assumed that the properties of the follow-on product actually are?
With the exception of biosimilars, regulatory strategies have been put in place retrospectively. In the case of biosimilars, scientific evidence and previous experience obtained with biotherapeutics was guiding regulation, which was actually put in place before market authorisation for the first biosimilar was requested. This is, however, not the case for NBCDs, as some products, regulated through the generic approach, are already on the market.
No specific regulatory pathway was present at the time when, for example, iron sucrose (IS) was submitted for marketing authorisation, so the manufacturers “did their best to satisfy FDA requirements”. Today, with several nanomedicines on the market, the EMA and FDA still do not have a clear definition of how ‘nanoformulations’ actually are defined. Inconsistencies in batch production make the establishment of pharmacopoeial standards a very challenging task. A rulebook has yet to be published, but with the science constantly evolving, opinion paper drafts are released for feedback from the scientific community and stakeholders.
However, because nanoformulations – some not really new developments but being a result of lifecycle management of old drugs – are ‘the next big thing’, companies are rushing to get on the market, which may leave authorities overwhelmed. The FDA therefore made a conscious decision to not allow IS products on the market prior to obtaining results from a comparative study between originator and an IS intended copy. The decision was a difficult one because it was taken on a rather small database of only one clinical report, but suggests that FDA is aware of the specific challenges related to nanomedicines. In Europe, EMA has released a draft of a reflection paper that should be read in conjunction with guidelines pertaining to regulation of biosimilars. In this respect, nanomedicines may be regarded in the same way as biosimilars. In how far the term ‘nanosimilar’ may be attributed to follow-on nanomedicines remains to be determined.
The economic pressure in health care is very high; however, many medical needs are not yet covered. Nanotechnology may assist in rendering ‘old stuff’ into more efficient and safer drugs, which will also be more cost-effective. Decision makers should be supported by information on the drug side supplied to them by pharmaceutical scientists.
Scientific challenges concerning nanomedicines make it unlikely that significant investment will occur unless the time to recover a return on investment, limited under current patent agreements, is extended. It is uneconomical for companies to put significant resources into projects characterising nanomedicines, which potentially triggers concerns around the patent life of medicines. Should the patent life of a medicine be extended to trigger the prospect of a return on investment to yield the potential benefits nanomedicines have to offer?
Example: the use of iron
Consider iron as an example. Iron deficiency anaemia is a global problem, with about 25% of the world’s population suffering some form of iron deficiency. In theory, treatment of the condition ought not to be problematical. Iron is cheap and plentiful, and ferrous sulphate is easily made into tablets. The problem with using oral iron preparations are that elemental iron is not well absorbed from the gut, meaning treatments to correct deficiency are prolonged, and side effects (for example, GI tolerance or constipation) significant, sometimes to the point of treatment failure because of non-compliance. It takes a long time to correct anaemia with oral iron preparations. Iron injections are an alternative, and intravenous preparations are used, especially in chronic kidney disease. The problem with iron injections has been pain at the injection sites for intramuscular use, or the risk of anaphylaxis (rare but potentially fatal, especially reported for dextran derivatives).
Newer, more stable iron carbohydrate compounds, such as ferric carboxymaltose, can be used in high doses of 1g or more to treat iron deficiency or anaemia in chronic kidney disease, and can be injected over short time periods (100mg/min), and is more effective than standard treatments of oral iron. There are 12 licensed iron injections across Europe, many based on complexes of sucrose or maltose, but as mentioned above, different nanoparticles can trigger different reactions from the immune system, thereby not allowing the use of chemically comparable IV iron compounds. There is potential to develop an oral nanoparticle iron preparation that is absorbed easily from the gut, based on the fact that modified ferritin molecules of 2–5nm have very good oral absorption compared with ferrous sulphate. But how would this be characterised, and how would Government Product Registries of products work when differences are due to characterising the shape of such small particles to identify the significant features that create differentiation? The regulatory framework is not yet ready to address these questions.
Technology worth pursuing
There are many potential benefits, for example, in cancer ,and in surgery. It may be possible to create a nanostructure that would support the regeneration of the part removed by changing cell processes that would fill in the surgical losses. This would mean return of physiological or structural function of that body area post-surgery, which may be lost using present methods. Surgery itself could be transformed as gold-coated nanoparticles can be used as ‘flash-welders’, (using a pulse of light to activate the nanoparticle) gluing incised tissue together without the need of sutures, particularly in anastomoses.
Treatments for macular degeneration in the retina typically involve multiple injections into each eye. By the use of nanomedicines, it may be possible to instill the medicines as drops, and target them to the retina, a much simpler and safer procedure.
Nanotechnology may have the potential to increase the shelf life of blood, by preventing its degradation more effectively than citrate. Likewise, immunology is a good area for the application of nanotechnology, and is subject to discussion in vaccinology. However, the problem is still the characterisation of the nanomedicine, and until this problem is resolved, the potential will remain unfulfilled. There is a whole array of autoimmune diseases that might become much better managed using this technology. These would include rheumatoid arthritis and multiple sclerosis. Nanoparticles can be used to deliver peptides to reset the immune system. In asthma, it may be possible to switch off mast cells to prevent release of the mediators of asthma attacks. In osteoporosis, bone cracks could be targeted by nano-aledronate.
The potential to target antibiotics will mean even current antibiotics could be rendered more effective. There is currently alarm that in future years, bacteria will become resistant to antibiotics, creating problems in areas currently taken for granted as treatable, for example, prophylaxis in surgery. Other areas that could have huge morbidity benefits globally would be the development of treatments for malaria, tuberculosis or HIV using nanotechnology. Not only would target sites for the drug be more specific, but also getting the drug into tissues would be improved. In HIV, it is difficult to erase the virus from the brain completely due to poor penetration, making it a ‘sanctuary’ for the virus using present methods.
Nanoparticles of a size <20nm should be able to pass through the blood–brain barrier easily. Other areas of novel therapy may include using RNA molecules to modify gene expression on nanoparticles.
Role of the hospital pharmacist
The challenge of nanomedicines means that hospital pharmacists will need to be aware of how the nanotechnology not only potentially enhances clinical benefit, but also may enhance toxicity, and, as a result, how they approach clinical practice. This will feed into the clinical and procurement aspects of a hospital pharmacist’s work. For example, the regulatory framework will need to be refined to better identify a nano particle medicine from a non-nanoparticle medicine. They can no longer be considered equivalent or generic from a procurement perspective. Pharmacopoeial tests would expect to show significant area-under-the curve variation when looking at bioavailability of products. Increased bioavailability might increase toxicity, so hospital pharmacists would need to be alerted to these possibilities. This makes the characterisation of nano-particles crucial as certain characteristics might prompt a particle to be more active or more toxic, depending on the circumstances.
The potential of nanomedicine will remain untapped unless the problems of characterisation of products, as a basis for rational regulatory strategies, remain unsolved. The problem will be solvable, but why would a company spend a lot of resources ensuring its manufacture of nanomedicines was consistent, for the relatively short time of the remaining patent life from which it might re-coup its investment. It may be that to achieve the benefits nanomedicines can bring, we have to recognise that there is a significant level of technology to be developed to bring such products to market, and that manufacturers will need an incentive. The easiest element to change is the patent life of medicines, giving industry a means of funding the investment needed. This is a very important consideration, and the potential benefits of nanomedicine mean we should look at all ways of developing these new medicines.