The economic crisis in Greece has dominated headlines in Europe for the past few years. The country recently secured a bailout worth €130 billion, but no one believes this will solve the crisis given that previous bail out loans of €110 billion in May 2010 and €109 billion in July 2011 proved insufficient. Greece's public sector has been hit hard by the ongoing austerity measures imposed on it and even now the government is spending more than it can receive through taxes. This perilous state of affairs is having a wide range of negative impacts on society. Unemployment and homelessness is rising, as is crime, and there have also been outbreaks of violence on the streets. 

The economic crisis has devastated the Greek healthcare system, with austerity measures introduced by the government resulting in significant budget cuts for hospitals. The Greek healthcare system was already suffering from understaffing and under resourcing before the crisis. Now, treatment waiting times have increased further and many people are turning to street clinics that had originally been set up by non-governmental organisations for those outside the mainstream system. Médecins du Monde has estimated that the proportion of Greeks now seeking medical attention at such street clinics is around 30%. Before the crisis, it was only 3–4% (1). There have also been warnings of a rise in infectious diseases such as tuberculosis, malaria, hepatitis and HIV (2). These findings are a shocking development considering that the Greek healthcare system was highly ranked by the World Health Organization in 2000 (3).  

Another sign of decline in the country's healthcare system is the disruption of the pharma supply chain. The government cutbacks have resulted in shortages of many medicines around the country. In January, the Panhellenic Association of Pharmacists described 500 commonly used drugs as being in short supply, including painkillers and products for hypertension, gastroenterological disorders, kidney disease and cancer (4). A commonly cited point in the media was that some pharmacies had even run out of aspirin (5). 

Previously, strikes by pharmacists had accounted for drug shortages, but the current supply problems are more complicated. In 2011, the Greek government enforced heavy price cuts for pharmaceuticals. According to the new law, a drug's price is set according to the average of the three lowest priced countries in the EU. As a result, Greece's spending on pharmaceuticals only amounted to €4.1 billion in 2011 compared with €5-6 billion in 2010 (6). The national spending on pharmaceuticals for 2012 has been predicted to be around €2.8 billion. Recently, Greece's health minister, Andreas Loverdos was quoted as saying that excessive spending on unnecessary drugs amounted to a value of €1 billion per year (6). 

The government-enforced price cuts mean that wholesalers prefer to sell their stocks in other countries where they can make higher profits. The problem has also been exacerbated by public insurers delaying payments to pharmacies, which have then been unable to pay their suppliers. The lack of funding has been detrimental for the pharmacy sector. Out of the 12000 pharmacies that operate, 800 are facing closure and a further 200 have severe operational difficulties (4). 

Rather than keep their stock lying around in warehouses or waiting for payment from pharmacies, wholesalers are maintaining their business by re-exportation. In 2011, the amount that public insurers owed pharmacists exceeded €400 million (5). As payments can take three months, pharmacists recently announced that they could only supply medicines to patients who paid with cash. For many patients, this is impossible due to their financial circumstances. 

Media reports suggest that Greece has become a pan-European source for parallel trade products. Prior to the economic crisis, parallel trade was described as having plateaued in Greece because pharmaceutical companies had imposed supply quotas for the country. However, pharmacies in other countries often turn to Greece to replenish their supplies when they are low on stocks. In effect, the financial incentive to supply a drug outside Greece rather than for domestic customers is creating new clients across Europe. This situation has also led to cases of fraud where a bill is still submitted for reimbursement to public insurers as if the drug had been prescribed to a patient locally. Reimbursement fraud has been estimated by the European Federation of Pharmaceutical Industries and Associations (EFPIA) to cost Greece more than €500 million, which places further strain on the healthcare system (5). 

Many drugmakers are adopting a negative view of Greece's pharmaceutical market, which is also contributing to difficulties. On the one hand, companies have to conform to the low prices demanded by the government, but then they also find their own products in circulation in other European markets. Consequently, some manufacturers have stated that they are competing against their own products in these foreign markets (5). Another concern has been the influence that Greek prices might have on the way other countries set their prices. As some countries use Greece as a reference point, there could be a steady lowering of prices throughout Europe. 

The restrictions of the Greek pricing system were so severe when first introduced that some manufacturers started to reduce supply. In 2010, Novo Nordisk took some of its insulin products off the Greek market, claiming that as well as price cuts reducing profits, it was also owed around €26.1 million by the Greek government (7). An estimated 50000 diabetic Greek patients were using these products and the company's move led to an outcry. Novo Nordisk responded forcefully, accusing the government of mishandling the economy and putting patients and the company in the difficult position.  

Another Danish company, Leo Pharma, took a similar approach and issued a Notification Letter of Discontinuation covering the potential withdrawal of 18 of the company's 29 products on the Greek market (8). The company also claimed that it was owed $300 million (€223.4 million) by the Greek government. However, Leo Pharma was particularly worried about the impact of Greek prices on pricing decisions in other countries that use Greece as a reference market. 

In 2011, Roche halted delivery of some of its anticancer products and other therapies to some of the public hospitals that had not paid their bills (9). It stated that some hospitals had failed to pay the company for more than four years, but that it was boosting supply to pharmacies that had been reliable clients. In general, privately-run pharmacies have had a better track record of fulfilling payment than public hospitals. Patients could take their prescriptions to these pharmacies and, in the case of intravenous or injected cancer drugs, take them back to a hospital to have them administered. In this way, the company believed that patients would not be deprived of their medicines. 

Representatives of the Greek pharma industry have also complained about the government's attitude (9, 10), arguing that pharmaceuticals only account for a small proportion of the healthcare expenditure and that little is being done about other aspects of spending, such as diagnostic tests and medical procedures.  

As Greece already has some of the lowest prices in Europe, the government has already exhausted all possibilities to extract savings from medicines. They have also stated that the pharmaceutical industry understands how critical the current circumstances are and the need for flexibility, and therefore seeks sincere dialogue with the authorities. However, the representatives add that the current approaches being used will do nothing to resolve long-term problems. It has also been suggested that the government is basing its decisions on flawed data. One recommendation was to harness the benefits of information technology so that a full picture of the waste in the healthcare system could be revealed (9). By studying the way in which the supply chain was monitored from product distribution to use of medicines by patients, the effectiveness of the whole system could be improved. 

The situation in Greece continues to look bleak. As it is unclear what comes next for the economy as a whole, it is difficult to see how the healthcare sector will receive improved funding. In the short term, Greece will remain an unattractive market for companies seeking to launch innovative medicines with high prices. However, pharmaceutical companies already have experience of operating in tough markets. They will likely continue their presence in Greece, but will be highly selective in the products they bring to market there.			

1. A. Kentikelenis, "Health effects of financial crisis: omens of a Greek tragedy" (Lancet website, 2011) 

2. A. Carassava, "Euro crisis: Why Greece is the sick man of Europe" (BBC News website, 2011). 

3. Healthcare Economist, "Health Care Around the World: Greece" (Healthcare Economist website, 2008). 

4. E. Karamanoli, "Greece's financial crisis dries up drug supply" (Lancet website 2012). 

5. N. Kresge, "Greek Crisis Dries Up Drug Supply as Even Aspirin Can't Be Found" (Bloomber GusinessWeek website, 2012). 

6. Pharmaceutical-Technology, "Greece confirms state pharmaceutical spend" (Pharmaceutical-Technology website, 2012). 

7. Pharmalot, "Novo Nordisk Pulls Insulin From Greece Over Money" (Pharmalot website, 2010). 

8. L. Taylor, "Danish drugmakers' "no" to Greek price cuts" (Pharma Times, 2010). 

9. A. Roy, "America's Future? Greece Defaults on Cancer Treatments in State-Owned Hospitals" (Forbes, 2011). 

10. C. Papachlimintzos, "Medicine in Greece is cheap" (Athens News, 2011). 

Articles

Industry Insider

Greece’s economic crisis has battered the country’s healthcare system, resulting in medicine shortages, market withdrawals and falling profits for the pharma industry.

Greece’s Financial Crisis and Devastated Healthcare System

Q. What is magnetic vectoring and why is this approach different from other delivery technologies?

The concept of nanomagnetic therapy is based on the unique properties of magnetically responsive nanoparticles (MNP) responding to an applied magnetic field gradient. MNP are nanoscale, ferromagnetic materials that present spontaneous magnetisation in an applied magnetic field, and exhibit rapid demagnetisation with no remanence when the field is removed. This superparamagnetism is, in essence, a magnetic (or biomagnetic as I like to call it) on–off switch that can be exploited in numerous ways to offer enhanced/advanced therapeutic options, ranging from early-stage diagnostics to medical imaging to localised drug delivery.  

The idea of using magnetic forces to enhance treatment therapies and improve therapeutic benefit has been around for many decades, but advances in this area are only now being realised thanks to the emerging field of nanomedicine and the application of nanotools to treatment modalities. 

Q. What is the potential for magnetic delivery systems in medical therapies? What progress have pharma companies already made in this area?

Magnetic-based therapies can be traced back through several centuries and, for the interested, an excellent historical review is presented in Magnetism in Medicine (1). Recent progress, with the development of smaller and more powerful magnets leading to highly functional miniaturised devices, has seen the expansion of magnetic applications across a spectrum of treatment methodologies that are being investigated in the clinic, such as cell separation, magnetic resonance imaging, enhanced gene transfer, localised targeted delivery of therapeutics or magnetically induced hyperthermia and early-stage cancer diagnostics. Recently, magnetic nanoparticles have also been applied to applications in tissue engineering and are being used to construct multilayered cell structures. In addition, applications in areas of allergy diagnosis are under study.  

One significant development is magnetically guided catheter technology, which is now used in cardiac stimulation and ablation therapy (2, 3). Although this is considered to be an invasive therapy, it offers the potential for site-specific drug delivery. In cardiac ablation therapy for the treatment of atrial fibrillation, where surgical procedures are indicated, a cardiac interventional workstation is used to navigate a catheter over short distances to the site of the arrhythmia. An extension of this procedure is the delivery of therapeutics to the site as well, being held in place using MNPs. 

The advent of functionalised MNP, such as ferromagnetic materials with superparamagnetic properties, has further opened new opportunities within the field of nanomedicine for targeted therapies. Progress in the development of nanomagnetic treatment modalities can generally be described as following two paths; one is based on implanted MNPs, where the oscillation of the particles provides the benefit, while the second path uses MNPs as vehicles or carriers for targeted therapeutics. 

Only a limited number of nanoscale therapeutic formulations demonstrating both enhanced solubility and drug targeting properties have received FDA approval (5). To date, however, nanomagnetic therapies have only reached limited clinical use (4). One drug targeting system for doxorubicin using micromagnetic (as opposed to nanoscale) particles, developed in the late 1990s, failed in clinical trials (6). Although presenting much potential, nanoscale biomaterials have been slow to develop into clinical applications. This can be attributed to a variety of reasons. The first is generally related to the physics of nanoparticles and the development of characterisation methods for understanding and preventing behaviour, such as particle interactions and agglomeration in the physiological environment. A second reason relates to methods for defining and understanding the biodistribution and specificity of nanoscale therapeutic formulations, which remains imperfect because of the body's complex response to nanoscale materials. Thirdly, it i difficult to find a delivery methodology for site-specific or organ-specific targeting. 

Recent advances in nanomaterial preparation and characterisation indicate that it is possible to overcome these limitations by using MNPs as drug carriers to improve drug localisation and overcoming cytotoxic effects. While magnetic targeting is not likely to be effective in all situations, with further development it should provide another tool for disease treatment. 

Although commercial success has been limited so far, the application of nanomagnetics to drug targeting opens a range of new opportunities for enhanced therapeutic performance, as described with magnetic vectoring (7, 8), magnetofection (9), magnetic hyperthermia (10) or with tissue vibration (11). These technologies are all at varying stages of development, but could deliver new therapeutic options for physicians and patients in the coming years. 

Q. How is nanotechnology applied to improve magnetic delivery systems? In which medical applications could it potentially be applied?

Magnetic vectoring can be considered as a two-stage process (at least), in which the MNP-drug construct is first caused to magnetically concentrate at a target site, such as a tumour, using externally shaped magnetic field gradients. Following extravasation where the potential for resistance to drug penetration (tumour interstitial fluid pressure) is overcome, the pro-drug is subsequently cleaved within the tumour microenvironment. Ideally, the MNP-drug construct remains nontoxic until cleaved within the tumour matrix. Additional components, such as affinity-based vectors, can be incorporated onto the construct for improved attachment and uptake (4). 

Nanoscale devices and carriers exploit the enhanced permeability and retention effect because they are small enough to traverse pores in the inherently disordered tumour vasculature. In addition, the 'nano' effect of increasing the surface area to volume–mass ratio with decreasing size enables high-drug loading on the particle surface. However, this advantage must be balanced with the retention of adequate magnetic susceptibility to enable magnetic deflection to successfully exit the vasculature. 

Current magnetic field technology already allows drugs to be applied to tumours at superficial sites (e.g., close to the skin or gliomas just underneath the skull) (4, 7, 8, 12, 13).  We also believe that innovation will enable magnetic field gradients to be constructed with the potential to manipulate MNP-drug constructs at visceral sites, such as the pancreas. It is also envisioned that this platform technology, in addition to localised drug delivery, will be able to open and close sphincters, aid hearing amplification and remediation, and promote controlled muscle movement. Using the biomagnetic switch concept, implanted MNPs can be used to drive tissue movement or vibration in response to an oscillating magnetic field (11). This concept can also be applied, for example, to the treatment of gastrointestinal reflux disorder by magnetically opening and closing the muscle, or in driving middle ear vibrations in response to an auditory input, or perhaps moving impaired muscle such as the blinking of eyelids. 

Q. When exploring the possibility of nanotechnology in a medical therapy, what are the potential safety concerns? How are safety issues monitored throughout research?

Safety concerns around nanomedicines have had persistently high visibility in the public domain—much more so than other therapeutics without the "nano" label. Concerns are based on the notion that nanoscale materials may distribute into and persist in anatomical compartments in a way that is not typical for other therapeutic agents. However, research activities, including those based on nanotechnology, are governed and monitored by regulators. At some point in the research process, very early on or after concept validation, the development effort will incorporate studies to address both biodistribution and toxicity effects. This early effort sets the stage for determining the potential viability of the methodology as it progresses through subsequent preclinical studies. 

Q. What tools, techniques, equipment and expertise are needed to conduct nano-enabled drug research? Given that nanomedicine is a relatively new field of research, how difficult is to find the right skills, experience and equipment?

Nanotechnology is an enabling technology, in which an ultraminiaturised process, procedure or application has the capacity to run better, faster, more efficiently or more effectively. As a nanotool, this concept can apply to technology development across the spectrum of scientific disciplines; thus, achieving a successful result also requires a merger of scientific skills/disciplines. To address this, both government and academic institutions have established various types of nanotechnology R&D centres/clusters for collaborative efforts, so that the range of required technical skills are seated in a single, discrete location. These clusters also house the expensive basic research and characterization tools, such as atomic force microscopy, electron microscopy, x-ray diffraction, and magnetic instrumentation, which can carry research well through concept validation (14, 15). 

Scientists who can understand and merge the concepts and principles of nanotechnology with medicine to develop advanced treatments are definitely in short supply. A successful project in nanomedicine that delivers a new drug targeting technology can incorporate many disciplines including nanophysics, magnetic physics, organic/biochemistry, molecular biology and oncology. Finding a team can require a lot of effort. 

Q. Several innovative nanomedicine projects are currently being researched and developed. What is needed to push these projects further and accelerate development?

The commercialisation of nanobased products and technologies is still mainly being conducted through start-ups and technology business ventures. These small business units typically take an early-stage technology from a university and, over a period of several years, attempt to acquire an intellectual property position that can attract major investor and development capital. Concurrently, the venture has to develop a feasible path through clinical trials and regulatory clearance. Because of the complex business relationships required, the cost to establish an intellectual-property base, the cost to conduct the fundamental research to get to clinical trials, and the uncertainty of regulatory requirements for nanoscale therapeutics (e.g., is it a device or a therapeutic?), many nanobiotechnology ventures end up in the "Valley of the Shadow", perhaps due to circumstances simply beyond their control. 

Realistically, the usual criteria still apply in terms of a securing a new drug application for nanotechnology-based therapeutics. In part, these criteria include the following:								

Can the nanomaterial be produced with batch-to-batch purity and consistency under GMP conditions?  

What particular matters surround the stability and handling of the agent?  

Do the required animal toxicology studies provide an expectation that toxicities in human will be manageable? 

In addition, it's important to consider the current situation with regards to patents. In the US, for instance, there is a significant backlog of nanobased patent applications that continues to grow. These added uncertainties, coupled with an inability to deal with them, can lead to extended development times and higher costs before the venture can even acquire the resources to establish a clinical path. In a weak economy, early stage capital becomes virtually impossible to find. 

Q. Some have claimed that many Big Pharma companies are losing interest in nanoenabled drugs. Do you agree with this statement? 

In many cases, such people are referring to nanoscale-therapeutic formulations, which offer some incremental performance changes through enhanced drug solubility and/or affinity-based targeting. Almost from inception, however, there has been a considerable risk that the benefits of such nano drug formulations may have been too hyped and oversold. True breakthrough drug technologies arising from this approach have yet to materialise. It also worth bearing in mind that virtually all medicines and diagnostic agents previously available to clinicians, prior to the wave of interest in nanotechnology, were already nanoscaled. Nevertheless, the rational design of a new generation of therapeutics is firmly based on increased sophistication that allows for localised delivery via systemic administration, with minimal impact on normal tissue, as well as a growing understanding of tumour biology.  

Pharmaceutical interest will certainly increase with the development of treatment methodologies that provide for increased dosage forms, with higher concentrations of drug delivered to the target site. 

is Managing Director, ViCorp Tech LLC, and CEO, NanoBioMagnetics. (Edmond, OK USA). 

, Wilfried Andrä and Hannes Nowak, Eds. (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2nd ed., 2007). 

4. J. Klostergaard et al, Future Medicines: Nanomedicine (In press, 2012).  

7. J. Klostergaard et al., AIP Conference Proceedings (Germany, 2010) pp. 382–387 

11. C.E. Seeney et al., Biomaterials, 26(14), (2005). 

Interview

Charles E. Seeney tells us about the possibilities of nanotechnology and magnetism, and how a novel approach could improve localised drug delivery.

Achieving Localised Delivery With Magnetic Vectoring

There are no two completely identical units in operation anywhere. Even if the difference is only in the version of the operating software, we are always dealing with a unique piece of equipment. Lyophilisers are also one of the few equipment items that are constantly undergoing continuous, and often significant, design changes as manufacturers respond to the evolving needs of customers. In general, there is a global shortage of freeze-drying capacity, which has led to many companies outsourcing this activity. It is not unusual for small-scale production (development to clinical phase II) to be performed at one contract manufacturer, while large-scale (clinical phase III and commercial product) manufacture takes place at another.  

 Diamond Sky Images/Digital Vision/Getty images			

One of the principal issues facing manufacturers is the significant differences that often occur in lyophilisation equipment performance and operation at the development and production stages. Because of this, it is difficult to develop models for process controls linking critical quality attributes with critical process parameter that scale easily, or that can be transposed from one site to another. Quality by Design (QbD) is an initiative that is gaining much attention in the industry. However, so far there isn't much proof of concept for QbD in freeze drying. In the pharmaceutical industry, there have been several QbD submissions, but lyophilisation predominantly applies to biological products and by the end of 2011 there had been no submissions that included a design space for biological compounds, according to a personal communication I had with the FDA's Lucinda Buhse in March 2012 

The fact that freeze drying is mostly used for biological products also creates further challenges. Biologics tend to cost more and there are usually limited amounts of product available. Experiments with the freeze-drying process tend only to be used in early development, and even then they are performed on small scales. One key parameter that must be known is the eutectic point of the formulation, so that the melting point of the frozen product is known. Without this information, the manufacturer will not know when melt back could occur and develop a cycle that has enough safety margin to prevent melt back from occurring. 

Special Feature

There are no two completely identical freeze dryer units in operation anywhere.

The Freeze Drying Challenge

The EMA has launched a pilot for submitting centralised marketing authorisation applications electronically. The pilot began on Monday 12 March and is expected to run for four months. During this period, companies will be able to apply for initial marketing authorisation applications for human medicines, and variation and renewal applications for human and veterinary medicines using an interactive PDF form. 

According to the EMA, the pilot is a step towards using electronic applications as standard, using the Electronic Common Technical Document (eCTD) format. Electronic applications are expected to simplify and accelerate the application process by improving data quality and consistency during data entry, providing access to data in XML format and integrating application data with controlled terminology.

Depending on the success of the pilot, the PDF forms may become an alternative — and the recommended — format for submitting eCTD applications to the EMA. The forms were developed in collaboration with the EMA, European Commission services and medicines regulators in EU member states, and their content is identical to that of the current application forms published by the European Commission in EudraLex Vol. 2. 

Companies wishing to participate in the pilot are being encouraged to register their interest so that they will receive any urgent updates. Details on how companies can take part are described in the EMA's 

Electronic Application Forms Pilot Guidance

Eli Lilly plans to invest €330 million at its Kinsale location in Ireland to create a new biopharmaceutical commercialisation and manufacturing facility. The investment will lead to 200 new jobs, as well as an additional 300 construction roles during the building process. 

The facility is planned to be approximately 24,000 ft

  and will produce treatments for illnesses such as cancer and diabetes. In a press release, Lilly's senior vice-president of global API and dry product manufacturing, Paul Ahern said, "This investment is part of Lilly's planned growth strategy and proof of our confidence in Lilly's pipeline of new products, many of which are derived from biotechnology." 

Eli Lilly first established its presence in Kinsale in 1981 and the facility makes APIs for several of the company's products. The latest announcement marks the second significant investment that the company has made at the site in recent years. In 2006, the company committed to invest €300 million in a biopharmaceutical and new-product commercialization facility. The new facility came on line in 2010, but is still undergoing start-up activities. It is expected to manufacture commercial products in late 2013. 

Ireland's investment agency, IDA Ireland, worked closely with Lilly to attract the investment. According to Ireland's Minister for Jobs, Enterprise, and Innovation, Richard Bruton, the government has recently outlined a range of measures that will be taken in 2012 to target high-end manufacturing and the health and life science sectors for growth and job creation. 

Several other pharmaceutical companies have invested in Ireland recently. Most recently, Abbott Laboratories announced an €85-million investment at its manufacturing facility in Sligo at the beginning of February 2012. In September 2011, Pfizer and Merck & Co. invested €145 million and €100 million in Irish pharmaceutical operations, respectively. 

Merck KGaA has announced measures to reduce costs and increase efficiency to ensure the long-term success of its business model. The measures are expected to result in workforce reductions across all businesses and regions. The measures will be implemented in two phases. 

GSK recently recalled 394230 bottles of its antihypertensive drug DynaCirc CR (isradipine) controlled-release tablets. The lots were recalled due to concerns regarding the level of cGMP compliance and procedural controls related to line clearance during the packing process at a US-based facility of Novartis Consumer Health, where the product was made. 

The FDA has released a draft guidance for direct-to-consumer (DTC) television advertisements in the US. Companies will have to submit their TV ads for FDA review at least 45 days before dissemination. After reviewing, the FDA can recommend changes to protect consumers or to be more consistent with prescribing information. 

GlaxoSmithKline and Daiichi Sankyo have formed a joint venture hey claim will create the biggest vaccines company in Japan. The joint venture will seek to improve access to vaccinations in Japan, as well as introduce new vaccines and create better and more convenient combination vaccines. The new company will be called Japan Vaccine Co., Ltd. 

News

EMA's electronic pilot; Eli Lilly invests in bio facility

Medicine regulatory agencies in the EU, US and Australia have been successfully collaborating for some time now with regards to GMP inspections of API manufacturers, but now they are seeking to further expand this international effort by looking to include additional partners. The initial pilot scheme ran from 2008 to 2010 and involved the sharing of inspection plans, reports and information concerning API manufacturers, as well as several joint inspections. The project was so successful that cooperation in these areas has continued. 

The current partners have agreed that clear criteria need to be established for any new participant to be accepted, as well as to maintain ongoing participation. To this end, the EMA has published a document entitled

 Programme to rationalise international GMP inspections of active pharmaceutical ingredients/active substances manufacturers 

that outlines the terms of reference and procedures for authorities to participate in the programme. Some of the points mentioned are that the reference GMP standard for inspections will be ICH Q7 and that participants will be responsible for ensuring that the appropriate confidentiality arrangements are in place. In addition, if an inspection results in regulatory action or license suspension, this decision will be shared with the other authorities. 

However, if a potential new partner does not meet the criteria listed in the document, they may still be accepted into the programme for the benefit of global health. In addition, nonparticipating authorities may still request access to inspections information. In this case, information sharing will be facilitated in a way that does not compromise any confidential information. 

The WHO has already agreed to become a new partner in the collaboration through its Prequalification of Medicines Programmes, which aims to make quality priority medicines available to those who need them and includes evaluation, inspection and quality monitoring activities. 

Medicine regulatory agencies in the EU, US and Australia have been successfully collaborating for some time now with regards to GMP inspections of API manufacturers, but now they are seeking to further expand this international effort by looking to include additional partners.

Greater International Collaboration

Q. What types of unique approaches and product knowledge are required when using a QbD approach?

 We need to find a more profound translation for experiments conducted in different scales of equipment. 

Successful freeze drying requires a sound understanding of both product and process related attributes, as well as the corresponding analytical tools used during product and process development to representatively measure them. When we look at the desired final quality characteristics of a freeze-dried product, the term 'quality' is, in the first instance, unrelated to the stability of an API, but targets other characteristics, such as cake elegancy, reconstitution time, moisture content and other parameters. A vial with a collapsed cake is routinely rejected from the batch during optical inspection, even though API stability may be perfectly acceptable from a pharmaceutical point of view. Optical inspection is one of the first tests to be performed on a freeze-dried product, not API stability.  

 Henning Gieseler (University of Erlangen-Nuremberg)

The connecting link between 'quality attributes' and 'product/process attributes' is often grounded in the physicochemical behaviour of the formulation, which is a function of temperature and time. Physicochemical properties, such as the critical formulation temperature (the glass transition temperature of the freeze concentrated solute (Tg') for amorphous products or the eutectic temperature (Teu) for crystalline materials) are important parameters that must be determined prior to cycle development. Then, the goal is to control product temperature at the ice sublimation interface below this critical temperature during the cycle to avoid elevated mobility in the system and morphological changes, such as shrinkage, collapse and melt. In industry, differential scanning calorimetry (DSC) has been used for decades to assess the thermal fingerprint of a material. DSC is a powerful tool, but not perfectly representative for the real freezedrying situation of a product. A more representative procedure is the determination of the collapse temperature (Tc) by freeze-dry microscopy (FDM). The technical set-up of an FDM experiment is currently the best way to simulate freeze-drying in microscale, but still presents obstacles in data interpretation. 

Bearing these critical temperatures in mind, freeze-drying demands reliable and representative control of the product temperatures at the ice sublimation interface during primary drying to obtain a high-quality product. Many commercially available PAT tools (e.g., manometric temperature measurement, TDLAS and others) help during the developmental stage to determine product interface temperatures, but such tools can often not be used in a production environment. As a result, the biggest obstacle and challenge for the future when establishing a reliable QbD concept for freeze drying is to determine (relevant) critical product and process parameters that are also scaleable.  

 Lyohilisation has evolved a lot during the last twenty years. Years ago, lyophilisation development mainly relied on the skills of scientists who learned by a trial and error process. Today, analytical tools exist to assist the development of the freeze-drying process. For instance, apparatus such as a cryomicroscope enable the determination of the glass transition temperature, which is used to set up the temperature and pressure during the primary drying phase of a freeze-drying cycle. For a QbD approach, it is quite easy to define at which step each tool will apply and what will its output will be on the process. 

Today, the development of a new process is more systematic, which gives developers more time to concentrate on the product's specificity.  

At Baxter, the QbD approach to freeze dry cycle development and optimisation relies heavily on a process analytical technology called tunable diode laser absorption spectroscopy (TDLAS). This is a near-infrared technology that measures the instantaneous mass flow rate of water vapour from the chamber of the freeze-dryer to the condenser. We also use fairly standard methods for characterising the formulation, such as low temperature thermal analysis and freeze-dry microscopy, to determine the upper product temperature limit during primary drying. We use a graphical approach to the design space that incorporates limitations placed on the process that are based on both the characteristics of the product and the capability of the freeze-drying equipment. TDLAS facilitates measurement of the vial heat transfer coefficient as a function of the pressure, measurement of the resistance of the dried product layer to flow of water vapour, and the maximum sublimation rate supported by the equipment as a function of pressure. All of these are needed to construct the design space. 

 In any QbD process, it is important to first define the required performance of the finished product. In other words, what are the critical quality attributes of the product? For a freeze-dried product these are typically things like reconstitution time, appearance, shrinkage, collapse, viability of product and shelf life. 

The next step is to use analytical methods to determine the behaviour of the product during the freezing and drying process. A risk assessment technique, such as failure modes and effects analysis, determines which factors in the process can be expected to impact the quality of the final product.  

The basis of QBD is to make sure the level of knowledge regarding product and how product quality varies with changes in raw materials or variability in process conditions ensures that the process is fully capable of producing a product that meets specification. 

 Nearly all lyophilised products must be sterile, which imposes a critical quality attribute that is not relevant to oral products. Also, while stability is often an issue with oral products, it is nearly always an issue with a lyophilised product; otherwise, why lyophilise? In addition, Design of Experiments (DOE) is often a critical part of QbD. Although QbD can be useful for the design of formulations and processes for lyophilised products, it is not useful in the design of the primary drying stage of lyophilisation. This is a result of the fact that the physics of primary drying are well understood. Designing processes based on physics is better and more efficient than designing them based on statistics. 

Michael J. Pikal (University of Connecticut)			

Q. What key factors must be considered when determining design space?

 Design space should be defined for both critical formulation and process factors. Considering formulation, such factors could include the critical formulation temperature (i.e., the collapse temperature), moisture content, API stability parameters, appearance and morphological parameters. Most scientists, however, focus on the process design space, or more precisely the primary drying design space). Here, the most important factor is the product interface temperature.  

Recent studies have suggested that determination of the primary drying design space alone seems insufficient to draw a representative picture of product behaviour during the process. At the very least, the freezing step must be considered as well because it determines the pore size distribution and, therefore, affects mass flow resistance during primary drying. Moreover, the freezing step may cause API instability due to occurring freeze concentration or ice/water induced surface denaturation (proteins). A product morphology that has formed at different nucleation temperatures during the freezing step might also provide a different degree of stability to the cake structure during primary drying. For example, warmer nucleation temperatures form bigger pores. Some product cakes have shown a higher structural firmness during the sublimation phase when bigger pores were present. The product morphology formed during the freezing phase even influences the secondary drying performance of the drug product. 

The biggest obstacle is to representatively determine the formulation and process design space. While the process design space is typically defined in laboratory-scale equipment, such information must then be scaled to manufacturing. The challenge is then that the originally defined process design space might not perfectly match the process design space in manufacturing. 

 The key factors to determine a freeze-drying process are temperature of the shelves, pressure in the chamber and time. The value of these parameters is influenced by the equipment, which means the design space should be as large as possible. For the output parameters of the process, the key factors are cake elegance, moisture content and potency. Depending on the product, some specific parameters can be added. For example, if the active ingredient is prone to oxidation a specific test can be developed.  

The key factors are the upper product temperature limit during primary drying (either a collapse temperature or a eutectic melting temperature) and the capability of the equipment. In addition to this, we need to know the relationship between the variables we control, such as shelf temperature and chamber pressure, and the variable we are most interested in, which is the product temperature. This is done using well-established equations for heat and mass transfer in conjunction with the vial heat transfer coefficient and the resistance of the dried product layer to flow of water vapour. 

At my company, we have directed most of our attention to design space development for primary drying, since it is generally the most time-consuming part of the process, and is generally associated with the highest risk to product quality. We also need to direct our attention to the freezing and the secondary drying phases of the cycle. 

The design space defines the acceptable processing conditions that have been shown to result in an on-spec product. Frequently, the concept is considered in terms of the allowable range of setting of the critical process parameters. However, it is also useful to use it to consider the range of process conditions that naturally occur inside a freeze dryer.  

The main paradigm shift that occurs currently within the lyophilisation world is to admit that each container has its own individual process, which is determined by influencing factors such as the position on the shelf or nucleation sources. This applies for all kinds of containers including vials, syringes or trays. 

Normally there are three types of constraints. First, you want to restrict the temperature of the product during primary drying to a value less than some maximum allowable temperature, which is frequently (but not always) the collapse temperature. Selecting the proper combination of shelf temperature and chamber pressure will ensure this goal is met, but the process should also at least close to the minimum time as possible to achieve the best process efficiency. Secondly, the time spent in primary drying needs to be sufficiently long enough such that all of the product will be devoid of ice before the shelf temperature is increased for secondary drying. Premature increase of shelf temperature may cause product collapse. Finally, the process needs to be run at a sublimation rate that is within the capabilities of mass and heat transfer for the system. Running under conditions that are excessively aggressive may, for example, result in choked flow, meaning loss of chamber pressure control and perhaps leading to loss of the entire batch. 

Q. How much consideration should be given to determining the edge of failure in lyophilisation process development and why?

 In my opinion, the 'edge of failure' is important to both know and understand in freeze-drying science. While processes or formulations should not be designed at the 'edge,' you can't estimate an appropriate safety margin that is required. In cases where the edge of failure has not been investigated, a safety margin might be too conservative, or defined on a trial-and-error basis. More importantly, for some critical process or product parameters, edge of failure conditions do not exist, which is then quite relevant. For example, a product that can be processed in primary drying at shelf temperatures well above ambient, the limiting parameter is not the product anymore, but the design of the equipment. Again, we should work with a safety margin in the established design space, but we need to rationally set the safety margin, based on the knowledge of the edge of failure.  

 It's interesting to know where the edge of failure is, even if it's nonessential data because it provides knowledge about the total robustness of the formulation. In a QbD approach, the extent of your design space comes from the risk analysis you used to determine the necessary margin. Let's imagine that for shelf temperature we define a 5 °C range around the target. For some formulation, 5 °C is near the edge of failure, but for others we have five more degree. From this value, different formulation can be ranked in term of robustness against collapse.  

We give this a great deal of consideration for the development of freeze-dried products. Our understanding of the idea of a design space is to know all of the combinations of, for example shelf temperature and chamber pressure, that result in a pharmaceutically acceptable product. We like for this design space to be as large as possible, so the boundaries of the design space are the upper product temperature limit during primary drying (that is, the edge of failure of the product) and the equipment capability, which is the edge of failure of the equipment. Therefore, we think the edge of failure is a key component in design space development. 

 The value of knowing where the process may fail is important. Determining the design space depends on the level of confidence in the rate of change of the relevant parameters in the region between the limit of the design space and the edge of failure. If a process is very predictable and linear, then risk of failure can be reasonably predicted. 

However, in a freeze-drying process the impact of the process condition on the product quality may be non-linear and prediction of the proximity to the failure edge less easily defined. In this case, it may be better to explore the edge of failure explicitly. 

In general, I agree with this philosophy. However, I maintain that with regards to the impact of collapse, it is advisable to freeze dry a product well above the collapse temperature to observe the impact on product quality. The reason is that collapse temperatures are determined using techniques that do not always quantitatively predict collapse in a product that is being freeze dried in a vial. Sometimes you can freeze dry 5 °C or more above the collapse temperature measured by freeze-drying microscopy without observable collapse in the vial. There are theoretical reasons and several observations that provide documentation for this statement. Secondly, even if collapse does occur in the vial, there is a question on whether or not any critical quality attribute is compromised. Often, the answer is no, and sometimes product quality (stability) is better in a collapsed product. The application of this information is the knowledge on assessing the risk of collapse. The measure of risk is really the product of the probability of the event and the severity of the occurrence of the event. Running above the collapse temperature addresses the "severity" of the occurrence of the event. 

Q. Changes in formulation and manufacturing processes during development and lifecycle management should be seen as opportunities to gain additional knowledge. Could you please give examples of how this principle can be applied?

 One of the best methods of gaining additional knowledge about the product and process is to implement robustness testing protocols during cycle development in the laboratory. Here, one would use the desired final formulation composition and desired (optimised) freeze-drying recipe and then develop protocols that challenge the cycle and the formulation. The shelf temperature is elevated in predefined steps to obtain higher product temperatures during primary drying. The same principle can be applied to the chamber pressure set point. After the cycle, the product-quality attributes are inspected and correlated to the observed process-performance attributes. The same robustness testing concept may be applied to the formulation stage. A change in excipient concentration or even exchange of single excipients typically results in a significant change of the formulation performance, and thus design space. The use of statistical methods, such as a Design-of-Experiments (DoE), helps us during formulation development to identify relevant factors. In general, DoEs are much more helpful during the formulation stage than during process development because of the number of experiments required.  

Overall, a gain of additional knowledge is certainly a desire for most formulation scientists or process engineers, but stringent timelines in the routine day-to-day work don't usually provide enough time to look deeper into the science.  

The role of stabilisers such as sugar, buffer, polymers and surfactant are now better understood. Nevertheless, depending on the complexity of the molecules, some surprises can occur during development that will need to be corrected. The knowledge gleamed from this will be remembered when developing new molecules. It is necessary to detect all the specificities of the molecule during the early stage of the development because at this stage it can easily be corrected without impacting results of clinical studies. Formulation changes in the late stage of a project can be a major concern. 

 We don't consider changes in the formulation in the context of life cycle management; that is, once the formulation is established, we don't make changes. However, during product development, making systematic changes in composition is part of the development of the formulation design space. This might be a plot of Tg' versus pH, for example. The idea is to get a good sense of how changes in composition affect the behaviour of the product. For examining stability, we generally rely on short term testing under stressed conditions. 

 In the past, quality control techniques have tended to consider and record only binary attribute data such as pass or fail/good or bad. This approach is often rooted in old-fashioned concepts of quality control by inspection of the final product. But if only pass/fail attributes are recorded, a lot of useful information about the parameter being measured is lost. By determining and recording actual measurements it is possible to apply simple statistical process control techniques that can characterise the capability of the process and give warnings of unpredicted variability long before the process reaches a specification limit. For example, measurement of shrinkage within an acceptable range may be a useful indicator that the process is moving closer to a point where an unacceptable level of collapse may occur. 

 I would like to think there are actual examples of industry implementing this advice and finding enthusiastic endorsement from the FDA. However, I have no direct knowledge of such examples. I do know, however, that many processes are run far from the optimal. If these were optimised, or at least improved using existing good freeze-drying practice, it would result in shorter processes with absolutely no increase in the risk of loss of product quality attributes. Indeed, in some cases, risk of loss of product quality attributes would be less in the redesigned process. In the formulation area, we know now how to formulate at least some proteins in such a way as to obtain far superior stability, with the amount of aggregation developing at room temperature storage for two years being far less than the aggregation that develops during two years at refrigerated storage. However, I have not seen any examples of a company reformulating to reduce the level of aggregates, as long as the "current formulation" meets the minimum product requirements.

Q. What analytical tools and techniques are essential for monitoring an enhanced approach to a lyophilised product?

An innovative PAT approach for freeze-drying would requires a PAT tool that allows the determination of a critical product parameter, such as product interface temperature and product resistance, for the batch as a whole (batch method). Ideally, the technology should be applicable in all scales of equipment. As a compromise, two different technologies (one applied in the laboratory, one in production) can be used, but they must provide a reliable and comparable measure of the same parameter without inherent scale factor.  

In addition to the batch method, a complementary single-vial technology is also necessary that allows a noninvasive measurement (no contact with the product) of a critical process or product parameter in a single vial. The reason for such a combination is simple. A batch method draws a global, average picture of the product drying performance, while the single vial method determines specific product drying performance at a given spot in the freeze dryer. This would help to delineate drying heterogeneity between vials (edge effects, hot or cold spots on the freeze dryer shelf) which is always present in a freeze dryer in whatever scale and which might even change over time in a given unit.  

One of the current weak points for freeze-drying is the absence of direct measurement during the process. In the past, product probes where used to monitor the freeze-drying cycle, but they were not really reliable. There are many reasons for this, but mainly they are invasive because as you modify the freezing of that vial (metallic wire), it creates some void around the wire that allow vapour to escape more quickly. Today, automatic loading systems mean that these probes cannot be used at all anymore. However, new PAT tools are appearing on the market.  

 As indicated above, we use TDLAS as the main PAT for design space development. It isn't essential, but it greatly decreases the time and effort required to construct a design space. We have found TDLAS to give accurate mass flow rates on laboratory scale equipment, usually within about 3% as compared with gravimetric determination. We do this by weighing the filled vials and stoppers before and after freeze-drying. However, TDLAS on production-scale equipment is considerably less accurate because of complexities in the dynamics of water vapour flow from the chamber to the condenser in large-scale freeze-drying equipment.  

Steven Nail (Baxter Pharmaceutical Solutions)			

 The most important aspects of understanding the process are those that give an insight into the experience of the individual vial rather than simply measuring the integrated effect on the headspace. Simple aggregated measurements, such as chamber pressure or more complex measurements like the application of mass spectrometers to the chamber gas, all have value for overall process control. 

To understand the range of process conditions caused by both forced and natural variation within the overall system of the equipment, the vials and the product, it is important to be able to characterise the range of experiences of individual vials. However, the problem is that techniques examining the individual vial that can be used during development and validation are frequently difficult to deploy in a large production dryer.  

 The key properties to measure are product temperature and primary drying time. Unfortunately, product temperature in given vials cannot be measured in a representative way. Insertion of temperature probes reduces the degree of supercooling, making the measured temperatures nonrepresentative of the batch as a whole. This problem can be circumvented, however, by using controlled ice nucleation, but although this technique is now available in both laboratory and production equipment, it is not routinely used in manufacturing. Hopefully, this will change in the near future. There are also indirect ways to measure batch average temperature, such as MTM or TDLAS that could be used in manufacturing (particularly TDLAS), but so far, this is not common practice. 

Lyophilisation is often necessary for pharmaceutical products to improve stability or shelf-life. However, the process can present difficulties, particularly when scaling up from the laboratory to commercial production. We bring experts together to discuss best practices for developing a lyophilisation process, including quality by design (QbD) and design space.

Pharmaceutical Technology Europe-04-01-2012

Greece’s Financial Crisis and Devastated Healthcare System

Achieving Localised Delivery With Magnetic Vectoring

The Freeze Drying Challenge

News

Greater International Collaboration

Freeze Drying: The Experts' View