The global economy and financial system is not in great shape. The European debt crisis rolls on and on, driving European economies into recession. China's growth has slowed to "only" 7%, but that slowdown is enough to reduce growth prospects of countries that export to China. India's economy is feeling the effects of institutional problems, such as corruption and poor infrastructure. The US economy is growing, but at a rate too slow to bring down unemployment.  

The apparent incompetence of political leaders has not improved the mood. The inability of the US Congress to address the nation's debt and economic issues and uncertainty surrounding the upcoming national elections have created great uncertainty and caused business executives to scale back investment and employment plans. The failure of European political leaders to resolve their problems has undermined investor confidence and created volatility in financial markets. Even in China, where the Communist party maintains a strong grip, the impending change in leadership has added an element of uncertainty. 

In the not-so-distant past, such macroeconomic developments would have had little impact on the bio/pharmaceutical industry. Global bio/pharmaceutical companies were generating large profits from patented blockbuster medications and pouring them back into expansive R&D programmes and investments in new laboratory and manufacturing facilities. People had to take their medicine and the effectiveness of drugs, such as Lipitor and Plavix, ensured that governments and private insurers would continue to pay for them regardless of price. Attracted by the returns on successful new pipeline candidates and flush with cash, investors poured record amounts of capital into early- and mid-stage companies.  

Today, having fallen over the patent cliff, the bio/pharmaceutical industry finds itself fully exposed to the vagaries of the macro-economy at a very inopportune time. Not only have companies lost the big profits from blockbuster drugs, but they also face increased pressure from governments and private payers who are desperate to reduce healthcare expenditures. Drug prices are being forced down, generic substitution is accelerating and it is increasingly difficult to get coverage for expensive new drugs.  

Smaller companies are being buffeted by the uncertainty in financial markets. Venture-capital funds have less money to invest as their traditional investors have become more risk-averse, and venture capitalists themselves have focused on less-risky investments with faster payoffs, such as social-media companies. In instances where they are still investing in bio/pharmaceutical start-ups, they are favouring companies with later-phase candidates with strong near-term prospects for out-licensing. Funding by way of initial public offerings is scarce. The number of bio/pharmaceutical initial public offerings is way down, and most have lost value since they were launched. 

These pressures could not come at a worse time for an industry desperately trying to maintain profitability in order to fund new product development. Pipelines at many bio/pharmaceutical companies are sparse and R&D operations have been notably unproductive despite significant cost-cutting. High profile drugs continue to fail at Phase III despite the "kill-it-early" philosophy that guides decision-making at most bio/pharmaceutical companies. 

So, instead of a stable macro-environment in which to transition to the next generation of products, bio/pharmaceutical companies must fight fierce headwinds to make progress. They have been forced to remake their business models not just to address the new scientific and clinical realities, but also to reflect their closer connection to a world that cannot afford to maintain the rapid growth in healthcare expenditures.  

The business model changes thus far have been dramatic. Global bio/pharmaceutical companies now pursue growth opportunities in niche products, generic drugs and emerging markets instead of traditional blockbusters. They are downsizing their remote R&D campuses while building their presence in urban centres of medical research where their researchers can be continuously exposed to new ideas and technologies (a model that other knowledge-based industries have long subscribed to). They are rebuilding R&D processes to more thoroughly assess new candidates before graduating them to expensive clinical development stages. They are re-engineering supply chains to reduce costs and increase security. Although still dependent on physicians to prescribe their medications, they are looking for ways to interact more directly with patients. 

If the fortunes of bio/pharmaceutical companies are now closely tied to the macro-environment, then so too are the fortunes of CROs and CMOs. CMO revenues and margins are directly impacted by the declining unit volumes and growing customer demands in that they help absorb the lower prices being paid by governments and insurers. Providers of preclinical toxicology and API process-development services have seen their revenues stagnate as more rigorous graduation criteria and decreasing venture-capital support have reduced the level of early-development activity. In these changing times, CROs and CMOs have two choices: they can continue their traditional strategies of passively bobbing up and down on the rising and ebbing tides of the industry or they can seize the opportunity to help bio/pharmaceutical companies deal with their increased exposure to the macro-environment.  

Clinical CROs have shown the way on how service providers can help bio/pharmaceutical companies adapt to their new realities. Although originally just a source of supplemental labour, they have come to set the standards for quality and innovation in the running of clinical trials. In particular, they have led the way in the use of information technology to revolutionise the way in which clinical data is collected and analysed. CRO-driven technology innovation has enabled faster review and analysis of clinical data, flexible trials designs and patient-reported data using mobile devices.  

Similarly, clinical packagers have been in the forefront of adopting sophisticated packaging and printing and logistics technologies and practices to reduce the costs of clinical-trial materials, while ensuring supplies get to patients in a timely manner. All of this has enabled clinical research to be conducted faster and more cost-effectively. 

CMOs have lagged behind other service segments in identifying technologies and practices that can help bio/pharmaceutical companies respond to the changing macro environment. In particular, they need to find more flexible and lower cost manufacturing solutions to address a medical marketplace that is more focused than ever before on managing total expenditures. 

The ability and willingness of CROs and CMOs to contribute to the remaking of the bio/pharmaceutical business model, and especially to the ability of bio/pharmaceutical companies to respond to the macro-environment, is likely to determine their long-term success. 

is president of PharmSource Information Services, Inc., and publisher of Bio/Pharmaceutical Outsourcing Report. Tel. +1 703 383 4903 Twitter@JinPharmSource 

Articles

Outsoucing Review

The weak global economy adds to the challenges of bio/pharma companies and their suppliers.

The Macro View

High-potency manufacturing is a niche, but specialised area that requires proper facility design, equipment selection, production processes and operator knowledge to safely handle and produce highly potent APIs (HPAPIs) and finished drug products containing HPAPIs. 

 conducted an industry roundtable to gain a perspective of these issues. Participating were: Joe Cascone, director of potent product pharmaceutical development at Metrics; Joe Nettleton, vice-president and director of operations at Cambrex's Charles City, Iowa (US), facility; Peter Müller, delegate of the Dishman board and member of the Carbogen Amcis management team; Theodore Iliopoulos, chief scientific officer at Euticals; Paul Doherty, chemical engineer, Sigma Black Belt, and plant manager at Ferro Pfanstiehl Laboratories; and David Bormett director of operations at SAFC.  

A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process. What are the key considerations in designing a high-potency manufacturing facility and in selecting equipment?  

 High-potency containment structures address both cross-contamination requirements targeting patient safety and, at the same time, worker safety by maintaining occupational exposure limits (OELs) below 10 mcg (Band III) or 10 ng (Band IV) per cubic meter of air for an eight-hour weighted average. Exposure to just a small quantity of a HPAPI or highly potent compound can pose significant health risks.  

The challenge in designing a high-potency containment facility is to find the appropriate level of containment that should manage the exposure risk at a reasonable cost. It is also crucial that the operators and the production staff understand the need and proper use of engineering controls. Enclosed reactors, centrifuges, dryers and highly dusty mills are key manufacturing assets in an API production line and, together with product-transfer systems, are key elements in a high-containment design. The most crucial issues in selecting the proper equipment are the containment of the process itself. In other words, one must ensure that no airborne particles are released to the ambient air and that product remains in the process piping used. Equipment and facility-engineering controls apply to all areas handling such compounds, not just manufacturing. It also refers to process-development and quality-control laboratories. 

Proper initial design and engineering of a potent-compound handling facility is crucial to achieve the desired levels of containment. Consideration must be given for containment of the entire process, from weighing and charging of raw materials, to packaging of the final material. Key facility-design criteria include single-pass heating, ventilation and air-conditioning (HVAC) systems, controlled access to areas, airlocks around potent-compound handling rooms for segregated gowning/degowning, proper room-pressure differentials for containment, degown misting showers, bag-in/bag-out filtration components, sufficient support utilities (such as supplied air) and proper waste-handling capabilities. 

SAFC uses an overall potent-compound handling system that incorporates five levels of cascading protection, with the first two being the primary methods of material isolation/containment:  					

: using closed-system glassware and reactors and alpha-beta/split butterfly valves.

: glovebox isolators, ventilated laminar-flow enclosures, rapid-transfer ports, local exhaust ventilation and closed-system cleaning through clean-in-place (CIP) systems.

: proper air pressurisation, high number of air changes, single-pass air, restricted room access, airlocks, safe-change filters and misting showers. 

: As a secondary precaution, Saranex coveralls and hoods, powered air respirators or supplied air, proper glove selection, and chemical suits when needed for solvents/reagents.

: training, written procedures/policies, education and employee-health monitoring.

When designing and selecting equipment, it is important to partner with vendors that understand isolation/containment and the requirements for potent-compound handling. In many cases, the equipment vendors can provide data from previous containment testing conducted using surrogate products. The equipment selected should be fit-for-purpose and provide the necessary flexibility to accommodate process changes, especially for multipurpose facilities. 

 In pharmaceutical manufacturing, there are two primary objectives for containment: to protect product quality and prevent worker exposure. There are underlying design principles that apply to all pharmaceutical manufacturing and analytical facilities at Cambrex. The operational goal is to maintain process isolation using isolators, sealed process vessels, dedicated piping, and single-pass, high-efficiency particulate air (HEPA)-filtered airflow. It also is crucial to design the ventilation system so that potentially contaminated air will flow downstream and away from the process area. Ingress and egress also are controlled to ensure both air and worker traffic moves in a single direction with minimal turbulence. Gowning/degowning vestibules, material pass-throughs and misting showers also are integrated into the flow. Upon ingress, disposable garments are donned, and upon egress, workers are misted with water to tack particulates to disposable garments, which are then discarded before exiting. 

With respect to exposure prevention, in many instances, the design strategy for quality protection is the same as exposure prevention. Process isolation using isolators, sealed reactors and dryers and HEPA-filtered airflows are all important. In some cases, however, pressure differentials that protect pharmaceutical quality may not be protective of worker exposure. For example, when opening an isolator, positive pressure in the isolator will prevent cross-contamination, but the pressure release will potentially expel particulate material toward the worker. In these cases, the engineering strategy may include a bag in/out system. It also may be appropriate to include extra personal protective equipment when transferring toxic or potent compounds. 

Mockups, training and verification also are key. Because all manufacturing process are different, it is important to verify that a given process design will function correctly and that operators are familiar with the process before a pharmaceutical product is actually manufactured. At Cambrex, it is common for the manufacturing team to develop and conduct mock handling exercises. These mock exercises may include the handling of surrogate pharmaceutical compounds followed by an assessment of potential releases and cross-contamination using wipes, air sampling and appropriate analytical detection. Naproxen is typically used as a surrogate because it has an extremely low detection limit and is easy to clean. At completion, mock exercises will demonstrate that process and containment equipment performs as expected, provide process ownership and training for operators, and identify potential need for design modifications to prevent cross-contamination or worker exposure. Cambrex routinely conducts equipment maintenance and equipment performance verification to ensure isolators, hoods, balance enclosures, airlocks and HEPA systems are working properly. 

 Carbogen Amcis has more than one site and has more than one production facility at its headquarters site in Bubendorf, Switzerland, but the concepts pursued with regard to containment are governed by one common philosophy regarding the handling of HPAPIs: the risks to be controlled regard the patient, the worker, and the environment. Therefore, we are analysing the whole lifecycle from the purchasing of raw materials (which may eventually be highly potent compounds) to the delivery of products and to the creation of waste, the whole set of buildings and installations involved and the whole series of applicable procedures and measures.  

The containment requirements are defined in view of the toxicological category (performance-based exposure limit [PBECL], OEL, or acceptable daily exposure [ADE], respectively), whereby Carbogen Amcis is working with a four-categories approach, and strict requirements are applied in case of Categories 3 and 4. They particularly involve with regard to production, separation of the ventilation (room and/or reactor exhaust, i.e., systems), HEPA-filtration of exhaust air, separation of the room (airlocks), pressure cascades, partial dedication of specific equipment to HPAPIs, completely closed processing and separation of the wastestreams. Thus, the focus is on avoiding carryover as well as contamination of the workers and the environment through production equipment (cleaning), through space and through infrastructure systems. 

The respective considerations are applied along the whole sequence of activities (i.e., the lifecycle). The details cannot be outlined here, but it can be said in a summary that they include gloveboxes or isolators, respectively, barrier isolation benches, laminar flows and flexible containment with all the activities subjected to their specific risk analysis. Personal protective equipment is eventually used as a safety backup during critical operations.  

The facility and equipment constitute the barriers between the high-potent active agents and their surroundings. A facility designed with one-pass air and multiple airlocks with cascading negative pressure differentials will, in conjunction with other controls, mitigate cross-contamination. Hard- and soft-wall isolation technology demonstrates sufficient containment for the manufacture of solid-oral dosage forms containing compounds deemed to fall within an occupational exposure band of 10 mcg /m

  (TWA). These systems may be verified by recognised industrial hygiene practices, such as the

 ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment 

Enclosing a particular process or unit operation is reasonably well-established by most equipment manufacturers and isolation specialists. A key challenge is linking the unit operations together with the proper conveyance technology. This is particularly daunting if there is a wide variety of equipment makes and models. It is generally easy to contain powders within a bowl or vessel. Charging and discharging those powders and transporting them to other pieces of equipment is more complex. Examples of conveyance technology that may offer solutions include vacuum conveyance and continuous-liner 'bag-out' systems. 

Another challenge related to isolation and containment centres on powder sampling. Process intermediates (e.g., blends and granules) need to be sampled to characterise in-process attributes and/or comply with prescribed regulations. Access to the product 

 properly designed and contained sample ports is essential. 

 First and foremost is the principle to not rely on 'moon suits' for the operators and instead have a strategy and philosophy to use engineering controls to provide proper containment. The key considerations are the OEL of the substance to be handled and, particularly for a CRO/CMO, the stage of the API and the scale of operation. The organisation should have a system in place that uses the OEL to establish the acceptable options available for facility design and equipment selection. For a CRO/CMO, the best and most economical means to handle a potent substance depend significantly on the stage (preclinical, clinical or commercial) and scale. For example, the best means of producing a preclinical small-scale API might be a combination of dedicated laboratory-scale equipment, disposables and a small isolator. In contrast, a commercial product produced at a 50-kg scale might require plant-scale equipment with validated cleaning procedures and test methods.  

Risk assessment, evaluation and mitigation

On an operational basis, what are key best practices to achieve the desired level of containment? What are key considerations for making the appropriate risk assessment, risk evaluation and risk mitigation? What types of metrics are used to monitor risk during operation? 

 Conducting a thorough risk assessment is the best practice to achieve a desired level of containment. It is important to note that 'more' containment may not be a 'desired level' of containment. Rather, the desired level of containment is derived from the need to protect employees and mitigate cross-contamination of drug products. The level of containment required in any instance should be technical and quantifiable. It is not speculative or derived from interpretation or opinion. 

A comprehensive risk assessment will determine what engineering, facility and administrative controls are required. A risk matrix may be developed for each step of the process. Each matrix will identify associated potential adverse events. Each potential adverse event should be quantified by calculating the product of its probability of occurrence by its severity. Risks cannot be monitored during a process, but actual events and exposures can. Proper feedback tools are essential to ensure the 'desired level' is appropriate and effective. 

Utilisation of properly designed engineering controls is the primary means for achieving the desired level of containment. It is important to understand the OELs or potential OELs of developmental compounds, for the product to be handled in the facility, and then design and test to meet 50% of the lowest OEL. Planning for containment at 50% of the OEL allows for variability that may occur due to different operators, process scales, material densities and/or equipment use. Proper containment should be confirmed by obtaining industrial hygiene air/surface samples and conducting testing for the specific compound being handled, or using a representative surrogate product. Data generated during industrial hygiene testing should be used to assess areas of greatest potential risk for exposure to allow for improvements and changes to be implemented to minimise the risk. Testing must be repeated over time to evaluate containment systems and processes and to ensure that equipment continues to operate at expected levels.  

Another key area for consideration is equipment cleaning following use with potent compounds. An effective and verified cleaning programme is critical to prevent potential cross-contamination, especially in a multiuse facility. Equipment cleaning also can be an activity for potential employee exposure. Therefore, CIP systems should be employed when possible, and monitoring should be performed during cleaning activities to verify that the OEL requirements are being met.  

Facilities handling highly potent compounds should have a compound evaluation and categorisation system in place in order to conduct appropriate risk assessments and communicate hazards. This is especially critical when working on developmental compounds that may not have an established OEL. The categorisation can be used to determine proper handling and containment requirements for the compound based on the systems in place within the facility.  

 A proper facility to handle HPAPIs should be designed considering technologies such as isolators, laminar flow hoods and local exhaust ventilation systems with air filtered before released to the ambient air. The air supplied to the rooms should be single-pass with proper air-pressure differentials to keep product-exposed areas negative to all adjacent areas or airlocks. Appropriately validated cleaning procedures should secure no cross-contamination with the next compound to be produced using same equipment or piping. ISPE launched the 

Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) Baseline Guide

, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross- contamination (2, 3). EMA followed with a concept paper, published in Oct. 2011, and suggests using "a more scientific approach...to establish threshold values" (4).  

In instances when the toxicity of a compound is not known, it must be treated as Band IV compound. Obviously, the best would be to determine the toxicity of a given compound prior to embarking in high-cost production set-ups. To minimise the risk and for extra safety purposes even if engineering controls are in place, personnel working with highly potent compounds should wear suitable personal protective equipment, including respiration equipment.  

Best practices in dealing with HAPIs are the availability and checking of material safety data sheet (MSDS) data for any compound used in the process, process hazard analysis, start-up, safety review, training, change control, emergency planning and response. Measurement of the dust during operation in the production areas is a key parameter in defining and checking the safety level at the operational level.  

 Risk management at Cambrex begins with training. All Cambrex employees granted access to areas that manufacture potent or toxic APIs must participate in training and become certified. Training follows a detailed risk assessment and risk-management framework that was developed in collaboration with the Cambrex toxicologist who is board certified and has extensive experience in risk assessment and with the Cambrex occupational nurse. Project-specific risk management recommendations are formalised by the toxicologist into a document known as a Project Safety Dossier (PSD). PSDs are formally reviewed by the manufacturing team before beginning work. In high-containment areas, new process designs are evaluated by certified Cambrex manufacturing teams in mock exercises that verify and document containment. Cambrex is guided by a four-band occupational exposure band (OEB) framework. Every molecule used to synthesise the API is evaluated separately and assigned an OEB. In some cases, where data is unavailable for a particular synthetic intermediate, Cambrex may conduct 

When making risk-management recommendations and decisions, Cambrex is cognizant that safeguards must balance the conflicting goals of mitigating exposure risk, minimising the ergonomic hazards imposed by unnecessarily conservative exposure controls, and quality considerations. Safeguards include integration of API-specific toxicodynamic factors into risk-management decisions, appropriate use of personal protective equipment and containment verification with good hygiene practices. 

 The best practices to be applied depend on the category and amount of the material handled and on the frequency and complexity of the operation in question. For Carbogen Amcis, we are working with dedicated equipment that is firmly installed in many instances and working with flexible containment approaches in others (e.g., when having to dismantle equipment in the context of cleaning or when having to be sure that eventual leakage could be controlled). A realistic assessment of the risk in question is important.  

Key practices in analytically monitoring involve swabbing surfaces (e.g., in the laboratory) as well as air-sampling during critical operations. Thereby, we are normally working with a combination of IOM samplers carried by the worker and of stationary samplers adequately placed to provide an idea of the eventual emission's distribution in space. We use surrogates right after installing new equipment and periodically perform analogous sampling and analysing (i.e, high-performance liquid chromatography) of the true highly potent materials to control routine operations later on. The key parameter to be realistically determined is the exposed person's potential daily up-take in mcg.  

 Before moving forward with any project work, a process hazard analysis (PHA) should be conducted. This PHA will evaluate all aspects of the technical challenge and incorporate information, such as safety data sheets, product use, OELs, short-term exposure limits, odor threshold, industrial-hygiene monitoring method and analysis, irritant or sensitiser, toxicological data, primary toxic effect, route/mechanism of exposure, warning signs of exposure, treatment for exposure, cleaning procedures, acceptable surface residual levels, deactivation procedures, flammability/combustability, applicability of transportation regulations, waste disposal consideration and other regulatory impacts.  

Even with the best facility design and equipment selection, the level of containment can be largely determined by operational practices. Therefore, a considerable amount of effort needs to be devoted to writing solid operating procedures, and providing operator training. The organisation should have a system in place that uses the OEL to establish the acceptable options for handling procedures and practices. In addition, industrial-hygiene monitoring should be used to verify that the combination of facility design, equipment selection and operational practices is providing the expected level of containment. Medical monitoring of employees should be included as a verification of the adequacy of the industrial-hygiene sampling programme.  

 What are some recent technological advances in facility and equipment design for high-potency manufacturing? 

 Many equipment vendors are pre-engineering their equipment to be contained whereas in the past this was considered an optional upgrade. New equipment is more modular in nature. Product-contact modules can be cleanly removed from drive units and disassembled and cleaned in remote washing areas. This reduces downtime and exposure risks.  

 There has been an increasing interest in the use of disposable containment options for potent-compound handling, especially for larger-scale operations. Disposable systems reduce the time for cleaning and can eliminate the potential for cross-contamination. They also may be used as secondary isolation around fixed equipment to improve overall containment of the process to meet lower OELs. Improvements in local exhaust systems, with proper filtration for potent-compound capture, also have been implemented to further reduce potential exposure to employees or the facility.  

The integration of two types of equipment, in some instances by two different equipment vendors, is also an area that has seen improvement. This could include engineering glovebox isolation equipment onto Nutsche filter/dryers or lyophilisers to allow for containment during discharge of potent compounds. 

 There is a growing trend in powder processing. Closed systems for powder handling and special valves are being developed along with engineering advances in the equipment used to contain the highly potent APIs or hazardous compounds. The term containment itself directs engineers in developing methodologies and structures to isolate the highly potent compounds. Charging materials to reactors, discharging a centrifuge, charging of a mill and packaging in closed systems are becoming popular practices in dealing with highly hazardous substances produced in multipurpose facilities. Traditional technologies are not easy to clean, and the risk of material remaining on the surfaces is too high. Disposables used in the use of closed system solve these problems, but have limitations with some solvents. Some examples of currently used isolation technologies using disposables are drum-sampling, dispensing, transfer sleeves, filter-change containment, decontamination and cleaning containment. The benefit is that with low investment, one can achieve the desired containment level. I am sure that the future development will be focused in the development of isolation technologies at the level of dust generation. 

With improved awareness and hazard recognition related to high-potency API development and manufacturing, there is a greater appreciation of proper risk management associated with HPAPI handling in general. Industry leaders are working to move away from administrative containment strategies to more robust engineering controls. Specifically in regards to micronisation of HPAPIs, Cambrex maintains GMP micronisation suites equipped with high-level containment engineering controls. These containment systems units have demonstrated performance to 1 ng/m

What I am seeing is a lot of small improvements to potent-handling equipment, such as better means of cleaning split butterfly valves that are providing continuous improvement in containment. These small improvements should not be underestimated in their beneficial impact.  

Special Feature

Experts share insight on facility design and operations for high-potency manufacturing.

Strategies for High Containment

Following an inquiry in 2009 that suggested the launch of various generic drugs was being delayed by anticompetitive business practices, the European Commission (EC) has been closely monitoring deals for potential breaches of the EU's antitrust rules. Recently the EC issued a Statement of Objections (a formal step in investigations into suspected violations of antitrust rules) for two further separate cases.  

The first statement was sent to Lundbeck and several generic-drug companies with the preliminary view that agreements were formed to prevent the market entry of cheaper versions of Lundbeck's antidepressant, citalopram. After patents on citalopram expired, the EC says that Lundbeck entered into agreements that involved "substantial value transfers" from Lundbeck to its generic-drug competitors, who subsequently chose not to market any generic versions of citalopram.  

"The value transfers included direct payments from Lundbeck to the generic competitors and also occurred in other forms, such as the purchase of generic citalopram stock for destruction or guaranteed profits in a distribution agreement," said an EC statement, released on 25 July. 

The second being scrutinised by the EC is Servier. The EC believes that Servier's agreements with several companies, coupled with acquisitions of key competing technologies, were aimed at preventing the market entry of generic versions of its cardiovascular medicine perindopril. Servier has been under close watch by the EC for potential anticompetitive practices since 2009. 

Despite these latest high-profile cases, the EC has reported a decrease in pay-to-delay deals. Results from the EC's patent monitoring activities show that the number of "potentially problematic" settlements stabilised in 2011 at 11% compared with the 21% noted during the sector inquiry, which examined the period 2008–2009. 

Stephanie Sutton is community manger of PharmTech Europe.

Following an inquiry in 2009 that suggested the launch of various generic drugs was being delayed by anticompetitive business practices, the European Commission (EC) has been closely monitoring deals for potential breaches of the EU's antitrust rules.

European Commission Investigates Pay-to-Delay Deals

Paediatric-drug development is an area that has lagged in terms of regulatory attention in the EU, partly because of the difficulties in establishing consistent regulations between the different member states. The US introduced its Pediatric Rule in the late 1990s, but the EU's own Paediatric Regulation (Regulation (EC) 1901/2006) only came into force in January 2007. The European Commission is preparing to report back to the European Parliament in 2013 on the 5-year experience with the Paediatric Regulation.  

Many drugs currently used for children in the EU have not been specifically tested in paediatric populations (defined in Europe as 0–17 years of age) during development because of the ethical concerns of involving children in clinical trials. In the EU, research papers have suggested that this is the case for over half of paediatric medicines (1). Most products are tested in adults, but not necessarily in the same indication as used for paediatrics because they are often prescribed to children off label at the discretion of physicians. The decision over what medicines to prescribe to children may also vary between member states because of differing national laws and regulatory systems.  

The Paediatric Regulation provides harmonised guidance and incentives for developing safe and effective paediatric medicines in Europe. The regulation requires all applications for marketing authorisations submitted to EMA to include either a product-specific waiver or a paediatric investigation plan (PIP) approved by the EMA's Paediatric Committee (PDCO). The PIP must contain a full proposal all paediatric studies, including their timings, the age groups concerned and all the age-appropriate formulations. In some cases, it is possible to defer the start of some or all of the paediatric studies until after a marketing authorisation has been granted (based on studies in adults).  

The regulation also offers incentives for paediatric development. Upon completion of an agreed paediatric plan, to the satisfaction of regulatory authorities, the medicinal product will be granted an extra 6 months patent protection through an extension of the duration of its Supplementary Protection Certificate (SPC). This incentive applies if the product is authorised in all EU member states and the relevant information from the paediatric studies (whether negative or positive) is incorporated into the summary of product characteristics. Interestingly, if such conditions are fulfilled, the extension will apply whether the data generated support a paediatric indication or not. Once a PIP is completed and has been validated by the regulator, a compliance statement is issued, which can be presented to the National Patent Offices. 

Another aspect of the EU's Paediatric Regulation was the establishment of a new type of marketing authorisation, the paediatric use marketing authorisation (PUMA), which was intended to encourage the development of off-patent products for use in paediatric populations. Only medicines intended solely for use in children are eligible for a PUMA, which, if granted (via the EU's Centralised Procedure), may lead to a new period of market exclusivity of 10 years (1, 2). 

In July, EMA presented a routine report to the European Commission (EC) on the companies that benefited from the Paediatric Regulation in 2011 (3). For 2011, EMA reported that its Paediatric Committee (PDCO) adopted 107 positive opinions on paediatric investigation plans (PIP), a similar number to 2010. The Agency is planning to reveal full details of these decisions later in 2012 (3).  

Statistics show that the introduction of the Paediatric Regulation has prompted greater drug development with children in mind. In 2008, 81 PIPs were agreed by the PDCO, but by 2009 this jumped to 122 (4). In a 2011 published analysis, it was documented that the highest number of PIPs were for endocrinology (13.4%), oncology (11%) and infectious (10.8%) and cardiovascular diseases (7.1%) (5). Overall, the proportion of paediatric trials as a percentage of all clinical trials was only considered to have increased to a modest extent, although it was suggested that this might be because more than 80% of paediatric trials had been deferred until after adult drug development (5). 

It has been suggested by independent observers that the impact of the Paediatric Regulation should be closely monitored to assess whether it meets the needs it originally set out to address (1). 

Authors in the US have expressed concern about the effect of the US Pediatric Rule because the paediatric studies reported to FDA did not necessarily address the most urgent needs in paediatric drug development (6). In the US, some of the major areas that received attention in terms of paediatric drug development were antidepressants and mood stabilisers, lipid-lowering preparations, HIV antivirals, and nonsteroidal antiinflammatory and anti-rheumatic drugs. These areas were identified as having more in common with the largest commercial markets for adult medicines rather the needs of the paediatric population. In particular, the authors reported that among the drugs granted paediatric exclusivity, there were 5 out of the "Top 10" prescription drugs with the highest sales figures in North America in 2005, generating combined sales of $24.1 billion (6).  

The authors also looked at the European situation and suggested that the EU approach to stimulating the development of off-patent drugs for paediatric use, through a PUMA, might go some way to counteracting industry's desire to focus only on drugs that were already generating considerable sales in the adult market. In general, they remained concerned that attempts by US and EU regulators to stimulate paediatric drug development may not have the desired effect and would be merely seen by pharmaceutical companies as a commercial opportunity to expand sales in existing adult market areas (6). 

In its July report, EMA commented that several companies had failed to comply with the Paediatric Regulation (3). In 2011, the number of delayed PIP applications was 44, which was an improvement over the 65 noted in 2010. However, the length of delay was greater in 2011 than it had been the previous year. Out of the 44 delayed PIP applications, only 4 were considered to have a valid justification for the delay. Twelve applications did not include any justification at all. While noting these delays, it is unclear from the report what action the EMA intends to take now against the offending parties. Apart from repeating the requirements that a PIP must be submitted in a timely manner, no potential punishments are actually detailed. The regulators only hint that the Commission Regulation on financial penalties (Commission Regulation (EU) No 488/2012) may be a future deterrent. 

European regulators are actively working to make progress on practical issues with respect to paediatric clinical trials. The setting up of the European Network of Paediatric Research at EMA (Enpr–EMA) in May 2010 was a key development (3, 7). Although it does not perform clinical trials, fund studies or research, or decide on areas for paediatric research, Enpr–EMA contributes to greater scientific understanding in the field and improves administrative competence at a European level. Enpr-EMA has members both inside and outside of the EU to represent various therapeutic areas, age groups and specific activities in paediatric medicine, such as pharmacovigilance. Enpr–EMA also holds annual workshops to discuss progress, with the last one being held in March 2012. At is 2012 meeting, Enpr–EMA discussions were still focused on how members could best collaborate and what approaches could be used to ensure representation from different stakeholders. Membership of the network is based on self assessment. According to the EMA's latest figures, 34 networks have submitted their self-assessment reports. At present, there are two networks that potentially fulfil all minimum criteria, but clarification over some issues is required before they can become members. Fourteen others still to meet the minimum qualifying criteria (3). The original deadline for networks to complete the self-assessment procedure was July 2010, suggesting that progress at Enpr–EMA is occurring slowly and it is too early to document an impact on paediatric development. 

The introduction of the EU's Paediatric Regulation has led to an increase in clinical trials involving paediatric subjects, but it is unclear whether the effects are what regulators initially desired. In particular, there is concern that the pharmaceutical industry is viewing the incentives as ways to expand sales for products that are already serving adult markets, rather than determining what paediatric medical needs are and prioritising these areas for drug development. From a practical perspective, Enpr–EMA promises much in terms of improving understanding of the field of paediatric drug development and ensuring that Europe has administrative processes conducive to approving such research. The EC is due to report to the European Parliament in 2013 on the impact of the Paediatric Regulation. This time may also be an effective point at which to assess progress with Enpr–EMA. 

1. M. Watzl, "The New Paediatric Regulation in the EU – Development, Implications and Comparison with US Experiences in Paediatric Drug Development" (German Society for Regulatory Affairs website, 2007), 

2. MHRA, "Medicines for children. Medicines and Healthcare products Regulatory Agency" (MHRA website, 2012), 

3. EMA, "Report to the European Commission: EMA/480331/2012" (EC website, 2012), 

4. P. Tomasi "The Paediatric Regulation as an instrument for European paediatric research. ENPREMA" (EMA website, 2011), 

7. EMA, "European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)" (EMA website, 2012). 

Industry Insider

Regulators in both the EU and the US have attempted to stimulate paediatric-drug development with incentives offering extended periods of patent protection, but are these actions having the desired effects?

Regulatory Intervention in Paediatric Medicines

A broad issue for single-use filter users and suppliers across Europe and North America is the pre-use integrity testing of sterilising filters in single-use systems. The subject has received considerable discussion lately, with differences in regulatory requirements and risk assessments being considered. The properties and suitability of gamma-radiation sterilised single-use filtration systems, and the flexibility of these designs, were not considered when regulatory guidelines were written, but now provide additional options for manufacturers. At the moment, there is no harmonised guidance on the pre-use integrity testing of sterilising filters. FDA does not formally require it, stating in its aseptic processing guidance that "Integrity testing of the filter(s) can be performed prior to processing..." (1).  

In contrast, the EMA states in EU GMP, Annex 1 that, "The integrity of the sterilised filter should be verified before use..." (2). So, while integrity testing after use is a common requirement, pre-use testing, whether before or after sterilisation, is not a universal requirement. This situation is further complicated in Europe where different national authorities apply EU GMP differently. Some European inspectors demand that pre-use, poststerilisation integrity testing be conducted because it is specifically required in EU GMP, while others are more flexible and do not require it.  

The topic was discussed during a workshop at the May 2012 PDA–PIC/S conference in Geneva. Arguments were expressed both for and against testing, but insufficient time was allotted to fully explore the technical issues and no resolution could be drawn. This situation leaves manufacturers with inconsistent international regulatory expectations, and more work is needed to ensure that inspectors have a common understanding. 

The issue is relevant to single-use disposable technology because EMA's published rationale for requiring pre-use, poststerilisation in integrity testing is based on the risks of filter damage or other loss of integrity during high-temperature sterilisation processes, such as steam-in-place or autoclaving.  

Hot topics at the IBC Single-Use Applications Conference			

EMA states, "The filter sterilisation process may be physically stressful for the filter. For example, high temperatures during the process may cause the filter to distort, potentially leading to fluid pathways that allow the passage of particles greater than 0.2 μm in size. The performance of a filter can improve with use, as particles begin to block individual pathways and remove larger pathways that smaller particles could successfully navigate" (3). 

Although such filter distortions have been reported for some prototype membranes, commercialised sterilising-grade filters are validated to maintain integrity and not undergo fluid path distortions (enlargement) during steam sterilisation that might enable initial bacterial penetration. Furthermore, sterilisation by gamma irradiation, which is typically applied to single-use filtration systems, can be considered a less stressful process (low heat, low pressure), and has not been implicated in the distortion of fluid pathways or loss of filter integrity so long as the membrane material is compatible with gamma radiation and that gamma dosage does not exceed specified maxima. These parameters are typically certified with every filter or single-use system lot. Many users question whether the possible risk of introducing contamination by performing a pre-use, poststerilisation integrity test on a sterile filter in a gamma-sterilised single-use filtration system is higher than the risk of not performing the test. 

The decision on whether or not to perform pre-use integrity testing should be made on a risk-assessment basis. Many users consider the filter manufacturer's integrity test prior to release to be sufficient confirmation that the filter is integral as made and is ready to use upon installation and sterilisation. It is rare for users to experience filter-integrity failures post use, so any user pre-use testing, before or after sterilisation, seems unnecessary. Experience with steam-sterilised filters, however, suggests that most instances of post-use filter-integrity failures, when they do occur, are due to gross filter damage incurred during poorly controlled steam-in-place or occasionally autoclave cycles. Where steaming processes are not well characterised and controlled to avoid filter damage, damage (if it occurs) can be recognised prior to product filtration if a pre-use/poststerilisation integrity test is performed.  

For gamma presterilised single-use systems, where the filter manufacturer has already validated that gamma irradiation does not compromise filter integrity, the risk of filter damage during sterilisation appears even more remote. The primary risk of product loss due to integrity failure of gamma-sterilised filters in a single-use filtration system would most probably be from filter damage incurred after sterilisation, for instance, during shipping, handling, and system installation. The lower risk of filter damage and product loss in this case may be further ameliorated if the process is a bulk filtration and, in the event of post-use filter integrity failure, refiltration is qualified and documented in the SOP.  

Alternatively, a redundant filtration scheme may be used to minimise risk of product loss in the event of a filter integrity failure discovered only postuse. Finally, the cost of the drug product or process fluid may be sufficiently low that an infrequent disposal is considered inconsequential (e.g., buffers and inexpensive small-molecule drug products).  

Although the potential for product loss due to filter nonintegrity may be very low, the effect can be great if the product is expensive and cannot be refiltered, such as with biopharmaceuticals and vaccines. Avoiding catastrophic batch loss, as well as possible product shortages, is a justifiable reason to perform pre-use, poststerilisation filter-integrity testing on single-use filtration systems. 

Another advantage of single-use systems compared with stainless steel is that versatile system designs can readily accommodate the necessary flushing to prewet filters before the pre-use integrity test. Stainless-steel tanks for the supply and collection of wetting liquid, which must be cleaned and steam sterilised in place, or autoclaved and aseptically connected, can be easily replaced with preassembled flush supply and collection bags that are gamma sterilised in place. Sterilisation validation is provided by the supplier. Where product is used to prewet the filter for integrity testing, even the side-flush collection bag can be eliminated in some cases. Additional schemes are also available to enable flushing the filter to reduce leachables and any particles that may be present on the downstream side of the filter, along with wetting them for pre-use integrity testing. Filters can be flushed with product to wet the filter, reducing filter leachables and potential particles while recovering the product to maximise yield.   

is senior vice-president of Global Scientific Affairs at Pall Life Sciences, Port Washington, NY (US), and chairman of the Board and Technology Committee at Bio-Process Systems Alliance. Tel. +1 516.801.9086 

Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice

Guide to GMP, Annex I — Manufacture of Sterile Medicinal Products

 (Brussels, Belgium, revised Feb. 2008, effective Mar. 2009). 

3. J. Wood, presentation at the IBC Single-Use Conference (San Francisco, CA, Jun. 4–6, 2012). 

4. J. Martin, presentation at the IBC Single-Use Conference (San Francisco, CA, Jun. 4–6, 2012). 

6. K. Lear, presentation at the IBC Single-Use Conference (San Francisco, CA, Jun. 4–6, 2012). 

Disposables Advisor

There is no harmonized guidance on pre-use integrity testing of sterilizing filters, prompting discussion among users as to whether such testing is necessary.

Pre-use Filter-Integrity Testing: To Test or Not To Test?

Earlier this year, I Holland and the UK's University of Nottingham launched a two-year Tabletting Science Anti-stick Research project. One particular issue that will be investigated is what makes formulations stick to tablet tooling surfaces, including why certain coatings resist sticking, whereas others do not. With sticking being an important issue facing tablet manufacturers, 

 spoke to Rob Blanchard, Research and Development Manager at I Holland, and Clive Roberts, Chair of Pharmaceutical Nanotechnology at the UK's University of Nottingham and Director at the Nottingham Nanotechnology and Nanoscience Centre at the University of Nottingham, to find out more about the collaboration.  

Q: What issues can tablet sticking cause during pharmaceutical manufacturing, and how well understood is this problem?

Sticking is a complex phenomenon created by different parameters such as Van der Waals forces, capillary action, electrostatics and the surface roughness of the tablet tooling, to name but a few. Sticking can reduce yields, double compression (causing damage to tablet press and tooling), and cause poor tablet appearance, inconsistent tablet dosage and inconsistent tablet hardness, as well as other production issues. Sticking should not be confused with picking, which can look very similar to sticking, but which can commonly be resolved by changing tablet design. In recent years, I Holland has seen increasing requests for assistance in solving sticking from both generics and pharmaceutical companies alike.  

Q: How do manufacturers currently address the problem of tablet sticking? Has the issue influenced the development of any new tools and technologies? 

A common way of reducing sticking is to slow the tablet press down, thus increasing the dwell time. However, this solution is unpopular with tablet manufacturers because it reduces productivity of the tablet press. As a consequence, tablet press manufacturers and tablet tooling manufacturers have introduced solutions to help the end-user reduce sticking issues in production. For instance, I Holland has developed a range of antistick coatings that have been successful in solving sticking, but the coating used should always be matched to the specific formulation. In the past we have worked in partnership with our customers to carry out trials using all the antistick coating solutions in order to match the correct coating with the formulation and environmental conditions. A potential issue with this method is the associated cost incurred in time and expense to find the correct solution.  

Q: With a variety of ingredients used in manufacturing, it must be difficult to systematically benchmark sticking behaviour for each ingredient. Can you talk about how the new collaboration between I Holland and the University of Nottingham aims to tackle this issue?

This is an important question and is in fact also complicated by orientation effects because the same material (if crystalline) can present quite different surface properties (chemical and mechanical) depending on preferential orientation effects. However, whilst building a library of data will take time, the range of excipients used in most formulations is not actually so extensive with the same materials (albeit in slightly different forms) often being used, particularly, with the high percentage content of solid dosage forms. Of course, APIs will be different and we will deal with the ones known to cause the most problems first and attempt to cluster compounds that have similar properties. Ultimately, the intention is to have a model that can predict sticking to various punch surfaces not based upon complex analytical measurements, but on a limited set of parameters that may largely already be known. 

Q: What techniques are necessary to further examine the intricacies of tablet sticking? How will the results of these techniques be combined to increase knowledge?

The project is exploiting a range of advanced surface analytical techniques to derive chemical and physical data from drug and excipients particles. The work also involves quantitatively mapping adhesion at the nano and micro scale using single drug particles, and links this adhesion data to actual tabletting experiments utilising a range of novel and controllable surface coated tablet punches with well‑defined characteristics. Multivariate analysis and principal component analysis will be used to identify the parameter(s) that influence sticking to form the basis of a model to predict propensity for sticking, based upon these factors. The ongoing use of the advanced techniques employed to collect the data in this research should not be required to implement this prediction in a commercial environment.

Q: Are there any particular areas that the collaboration will focus on? 

Previous research has focused on only a few excipients and therefore did not allow a predictive tool to be developed that would allow selection of the correct coating without the need of expensive and time consuming compression trials.The aim of I Holland’s research and development team is to speed response times to solving customers’ problems, ultimately offering better customer service. 

Ask the Expert

Rob Blanchard and Clive Roberts discuss the issues surrounding tablet sticking.

Tackling Tablet Sticking

Big Pharma Placed in Malpractice Spotlight

In August, Pfizer resolved investigations by the US Department of Justice (DOJ) and the US Securities and Exchange Commission (SEC) regarding corrupt business practices. The SEC charged Pfizer with violating the US Foreign Corrupt Practices Act (FCPA) after an investigation alleged that certain Pfizer subsidiaries in Bulgaria, China, Croatia, Czech Republic, Italy, Kazakhstan, Russia and Serbia had been bribing foreign officials to obtain regulatory and formulary approvals, sales and increased prescriptions. The bribes were concealed in accounting records as legitimate expenses for activities such as promotion, marketing, training, travel and entertainment and clinical trials. Pfizer voluntarily reported the violations to US authorities in 2004 and has since implemented anticorruption compliance reviews and anticorruption training.  

"Pfizer subsidiaries in several countries had bribery so entwined in their sales culture that they offered points and bonus programs to improperly reward foreign officials who proved to be their best customers," Kara Brockmeyer, chief of the SEC Enforcement Division's Foreign Corrupt Practices Act Unit, said in a statement. 

In addition, the SEC separately charged Wyeth, which Pfizer acquired in 2009, for its own FCPA violations. The violations are alleged to have taken place primarily before, but also after Wyeth was acquired. Pfizer discovered the violations shortly after the acquisition and reported them to the authorities.  

Combined, Pfizer and Wyeth will pay more than $45 million to settle the SEC charges, as well as a $15-million penalty from the DOJ. However, Pfizer has been praised by both the DOJ and the SEC for its cooperation with the investigations, and the DOJ has chosen not to push for any criminal action against the company. 

Pfizer is not the only big-name company to have been in the spotlight recently for business malpractice. In mid-August, Teva revealed that it was being investigated for potential FCPA violations. In July, the company received a subpoena from the SEC asking for documents concerning business practices in Latin America. Teva also added that it is conducting a voluntary investigation of its own into business activities that may have further FCPA implications. 

Meanwhile in July, GlaxoSmithKline was in the spotlight for marketing malpractice. The company paid $3 billion to resolve criminal and civil liability relating to several malpractices, including unlawful promotion of certain prescription-only drugs, failure to report certain safety data and false price reporting practices. GSK says it has taken action at all levels of the company to change its procedures for compliance, marketing and selling, as well as removing employees who engaged in misconduct.  

 asked whether drug settlements were enough to deter pharmaceutical companies from using corrupt business practices (see below). 

Do you think large drug settlements to settle criminal and civil liabilities are an appropriate deterrent to corporate malpractices?			

The majority of respondents (63%) believe that drug settlements are not enough an appropriate deterrent. However, large fines no doubt highlight to a business that it must do more to monitor activities across its global subsidiaries. In a statement, the SEC explained that Pfizer's recent charges "illustrate the pitfalls that exist for companies that fail to appropriately monitor potential risks in their global operations." 

Discuss the results of this poll and your thoughts on the recent FCPA violations on LinkedIn: 

Emerging markets continue to attract the attention of pharmaceutical companies thanks to their high growth and large patient populations. Back in 2001, the locations of focus were the so-called 'BRIC' countries (Brazil, Russia, India and China). Now, even with other markets gaining traction such as Turkey and Indonesia, recent announcements show that the original BRIC countries still retain favour with the pharmaceutical industry.  

 asked which countries, aside from China and India, pharmaceutical companies were most interested in expanding business operations into (see below). The clear favourite, chosen by 36% of respondents, was Brazil, followed by Other (19%) and Russia (14%). 

Into which pharmerging market - aside from China and India - is your company most interested in expanding manufacturing operations?			

Other announcements also suggest that Brazil continues to be an important pharmaceutical market. In July, Quintiles, a US-based contract services provider, opened its Global Commercial Solutions business in Brazil. The business offers customised sales forces, market penetration strategies and product solutions. In addition, the company has recently announced expansions in Russia, and the Middle East and North Africa region. 

Valeant Pharmaceuticals International has also invested in Brazil this year. In March, the company acquired a 19.9% minority equity investment in the research company Pele Nova Biotecnologia, which focuses on tissue regeneration. 

Abbott Laboratories signed an agreement in July for several R&D projects in Russia with the country's ChemDiv Research Institute (CDRI). The two parties will be principally be concentrating on improving formulations of Abbott's existing drugs. 

Pfizer has also been looking to Russia for R&D projects. In July, the company granted exclusive development and marketing rights to SatRx for their DPP(1)-IVi compound, which is being investigated as a potential treatment for type 2 diabetes. 

Novo Nordisk announced in April that it had started work on its new $100-million plant in Russia. The facility, located in Grabtsevo Technopark will formulate and fill insulin into the company's Penfill and FlexPen systems for the Rusian market. 

In August, Mylan announced that its subsidiary Mylan Pharmaceuticals Private has commenced commercial operations in India, beginning with the launch of a portfolio of 18 antiretroviral products for the treatment of HIV/AIDS. The company added that it will be looking to expand operations into the country with additional therapeutic categories. 

Also in August, the Indian pharmaceutical company Cipla announced that it would be investing in India by building facilities dedicated to active pharmaceutical ingredients in Patalganga, Bengaluru and Kurkumbh. The facilities are expected to be completed in 2012–2013. 

In August, Covidein announced the opening of its China Technology Center Research and Development facility in Shanghai. Covidien plans to invest up to $45 million over a three-year period into the centre. The facility includes laboratories, as well as a simulation suite that enables healthcare professionals to be involved in the medical device design and development process. 

In June, Eli Lilly said it would increase its equity in the Chinese drug-manufacturing company, Novast, by $20 million. Novast will use the investment to establish a platform that will support Eli Lilly's branded generic-drug products and increase the manufacturing capacity at its Nantong site over the next several years. 

Medicines at Top of EU's Counterfeit List

A report from the European Commission shows that fake pharmaceuticals were the top articles detained by European-Union customs in 2011. Customs seized almost 115 million products suspected of being counterfeit, up from 103 million in 2010. Approximately 24% (around 27 million) of these products were medicines, compared with just over 3 million in 2010.  

In 2011, there was an increase in the number of counterfeit items that could be potentially dangerous to health and safety (i.e., food and beverages, body care articles, medicines, electrical household goods and toys). Such products accounted for 28.6% of seizures, compared with just 14.5% in 2010. The EC report attributes the increase to the large rise in medicines. In general, the increase in the number of detained articles has been attributed to rises in postal traffic, of which medicines formed a large percentage. Approximately 36% of detained items in postal traffic were medicines. 

According to the report, China is the main source of the counterfeit products, accounting for 73% of all intellectual-property infringing items. The majority of the counterfeit medicines detained by EU customs in 2011 originated from China (68%) and India (28%). In 2010, almost all of the medicinal products identified by customs came from India (93%). In 2011, most articles were intercepted in Bulgaria, Italy, Greece, Belgium, and the Netherlands, compared with Greece, Italy, Spain, the Netherlands, and Portugal in 2010. 

MHRA Consults on Early Access to Medicines

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has launched a public consultation regarding a scheme that could provide patients with access to unlicensed medicines in Phase II or III clinical trials. The consultation will be open until 5 October. 

The scheme is expected to apply to medicines for life-threatening, debilitating, or chronic conditions that are at the end of Phase III trials or, in certain cases, at the end of Phase II. Research conducted by MHRA has shown broad support for such a scheme, particularly for patients suffering from life-threatening illnesses. 

If implemented, MHRA would review medicines that companies want to make available under the scheme and provide a scientific opinion on the risks and benefits. This information would help the country's National Health Service in deciding whether the medicine should be available early. 

"We have launched this consultation because we are committed to ensuring that where pharmaceutical companies want to make their new medicines available under this scheme, clinicians treating patients have access to robust scientific information to help them make appropriate treatment decisions," explained Kent Woods, chief executive of MHRA, in a statement. 

In its research, MHRA emphasises that patients will need to be fully aware of the risks of taking unlicensed medicines. There were also mixed views on whether early access to medicines should be given to patients with debilitating or chronic conditions, such as rheumatoid arthritis or diseases that may cause blindness. 

After receiving industry feedback, MHRA will aim to make a decision on implementing the scheme by the end of 2012. 

Patient associations have waded vigorously into the intense debate now starting on how to update the 20-year-old European Union regimen for pricing and reimbursement. Their intervention brings an additional dimension to the concerns voiced so far about this review of fundamental EU rules — notably pharmaceutical companies' fears that the outcome may mean tougher assessments of relative efficacy, or warnings from national health ministries that demands for faster decision-making are unrealistic. "The revision of the rules is important for patients," too, says the European Patients Forum (EPF) — which represents more than 50 diverse patient organisations, ranging from giants like Alzheimer Europe to smaller outfits such as the Malta Health Network or the Estonian Chamber of Disabled People. 

EPF has already drafted a position on the proposals that emerged from the European Commission last February, and gave its members until the end of July to comment. It wants to be sure it is equipped to maximise patient input into the formal debates on the new legislation that will start in the European Parliament and the EU's Council of Ministers after the summer break. So EPF is liaising with the Commission, key members of the European Parliament and what it loosely refers to as "other stakeholders" to prepare the ground for influencing the debates as proposals are turned into laws. 

The starting point of the draft EPF position is that "there are currently wide and unjustifiable delays in access to new medicines across the EU." One of its targets is the inconsistency displayed by national drug pricing and reimbursement regimes in Europe, which it blames for leading to inequalities in access to high-quality medical care 

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Big Pharma Placed in Malpractice Spotlight and other news from across the globe.

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Pharmaceutical Technology Europe-09-01-2012