Today's pharmaceutical companies are striving to reduce costs and maximise efficiencies, while simultaneously working to advance the core business as quickly as possible, and must make decisions on the best way to deploy their limited resources. The job of an operations manager for a modern pharmaceutical facility includes operating and maintaining outlying building services and the utilities required to create and sustain on-site manufacturing capabilities, energy management and essential non-manufacturing services, such as cleaning, building maintenance, catering and other ancillary services. Outsourcing some or all of these services is a proven solution to optimise efficiency.  

In out-tasking, pharmaceutical technology and manufacturing companies utilise third-party vendors to carry out various maintenance tasks on specialised equipment, such as water-for-injection (i.e., stills) or compressors and boilers, while leaving the responsibility for the quality and scope of the work and the internal documentation in the hands of the client. In contrast, when the operations and maintenance program includes regular, preventive and predictive work, as well as corrective tasks and technical support, then the client is operating under the outsourcing model. In other words, outsourcing involves contracting a whole function, rather than a specific task. Greater savings and efficiencies are found in outsourcing, rather than out-tasking.  

Implementing highly reliable energy solutions at research and manufacturing facilities is a significant challenge for pharmaceutical companies. The traditional model has been to run a facility with the company owning, operating and maintaining all equipment itself, thus assuming exposure to risk on issues such as equipment durability, fuel volatility and maintaining the expertise required to keep the system working properly in-house. Pharmaceutical facilities, however, are increasingly embracing the outsourcing model. 

The outsourcing service provider can be contracted to operate and maintain complex energy plants and ancillary equipment, such as: 					

on-site generation and cogeneration assets

steam, hot-water and chilled-water systems

After the outsourced service provider has been selected, the client and service provider should agree on a well-defined scope and clear objectives, which should be captured in a service level agreement (SLA). Using a risk-based approach, the scope and responsibility of the service provider can be built up over time, which will ensure client satisfaction, specifically around regulatory compliance. However, it is important that the client does not relinquish all responsibility, as the ultimate regulatory responsibility lies with the product manufacturer.  

Identifying a key subject matter expert to serve as a liaison between the service provider and client will ensure compliance to quality and regulatory systems. The expert should also design escalation and process flows for change controls and equipment deviation, which pose the most risk to the pharmaceutical manufacturer. For the service provider, customer satisfaction and adherence to quality systems in this highly regulated industry are essential.  

The client and service provider can develop a performance scorecard that is linked financially to the service agreement contract. Key performance indicators (KPIs) can include areas such as safe systems of work, system availability and performance against schedule. Each line item can be linked to a performance metric and each metric can be weighted with agreed-upon scoring criteria that is reviewed and scored on a periodic basis (e.g., monthly, quarterly). Linking the score to contract payments, by withholding an agreed-upon percentage each quarter, drives performance from the service provider's point of view and ensures client satisfaction. As the relationship between the service provider and client evolves, or as business expands, it is common to review and adjust the KPIs. 

Outsourcing maintenance allows the client to reduce costs without reducing core-business company headcount and, as the pharmaceutical company becomes the customer of the service provider, to more easily drive change and continuous improvement. Outsourcing also allows management to focus on developing and manufacturing the product rather than on the non-manufacturing activities involved in facilities engineering.  

Another key advantage of outsourcing energy management is that full-service outside providers possess the expertise to evaluate, design, build and then operate technologies such as combined heat and power (CHP) to optimise energy efficiency. CHP, sometimes referred to as cogeneration, is an efficient energy technology that simultaneously generates power (i.e., electricity) and thermal energy, which is used for heating, cooling and production of high-pressure process steam, while typically consuming only 60% of the fuel required for separate processes (1). 

 illustrates the higher energy efficiency of CHP compared to separate heat and power production. CHP technology is currently experiencing a resurgence in pharmaceutical facilities due to its many operational benefits. CHP can provide increased energy reliability, greater fuel flexibility and market responsiveness. CHP can also mitigate lost products and research projects due to utility grid failures. CHP reduces greenhouse gas emissions; the waste heat generated during the power production process can be captured, recycled and used for process applications without the need for boilers within each building.  

Figure 1: Comparison of separate heat and power generation with cogeneration. (Figure is courtesy of the authors.)			

CHP is a proven solution for industrial manufacturing environments, in which reliable power is crucial. According to the US Environmental Protection Agency's (EPA) Combined Heat and Power Partnership, 88% of existing CHP plants are utilised for industrial purposes (2). The other 12% are used by commercial and institutional entities such as hospitals, municipal and state governments, colleges and universities. With a full-service outsourcing provider, designing, building and operating complex energy infrastructure may be achieved seamlessly. 

Customers that implement CHP typically experience the following benefits: 					

Cost savings. Burning less fuel generates cost savings. CHP users avoid buying from the market at peak price periods. CHP can also be configured to use locally-sourced renewable fuels.

Reliability. Utility power outages will not interrupt CHP operations, so critical processes continue uninterrupted.

Environmental benefits. Greenhouse gas emissions and criteria air pollutants are reduced when less fuel is combusted.

Fuel diversity. CHP plants may be designed for input of multiple sources of fuel. This multi-fuel ability increases energy security and can also mitigate volatility in fuel commodity prices. 

Outsourcing may seem like a simple concept, but the potential benefits are significant, especially when complex energy infrastructure must be operated and maintained at the highest levels of reliability. Pharmaceutical research and manufacturing processes are costly to operate, so outsourcing the facility's energy plant operations and management can be a solution to control costs, reduce fuel and energy consumption and evaluate and implement energy solutions and technologies that can ensure the integrity of the underlying processes.  

is business development director for Veolia Energy North America. 

  is client operations manager at Dalkia Ireland's Pharmaceutical & Healthcare division. 

Articles

Manufacturing

Key considerations for outsourcing energy services.

Outsourcing Pharmaceutical Infrastructure Operations

The physical form of an API is important in formulation development for resolving issues in bioavailability and solubility. Particle-engineering technologies can be applied in various ways: crystal design for controlling crystallisation and producing cocrystals; particle-size reduction, achieved through jet-milling, wet polishing and nanoparticle generation; and amorphous solid dispersions, produced by several approaches, such as spray-drying, hot-melt extrusion (HME), spray-congealing and inclusion-complex generation. 

 discussed these issues with Colin Minchom, vice president, Particle Design Business Unit, at Hovione.  

: Under what type of situations would cocrystallisation be used? How does it facilitate the delivery of poorly soluble drugs?  

 Interest in cocrystals has increased in recent years, and the recent FDA guidance on a proposed classification of cocrystals has prompted further discussion and counter proposals from the industry. The proposed US FDA classification of cocrystals as crystalline materials containing two or more molecules in the same crystal lattice is limited but can serve as a starting point for discussion.  

The addition of a cocrystal former into the crystalline structure of the API changes its physical and chemical properties. It is possible, in some cases, to improve bioavailability to adequate levels while preserving the stability of a crystalline form. For APIs with low glass-transition temperatures, a cocrystal may be favoured over the amorphous form. As such, the use of a cocrystal may be an attractive platform to overcome the solubility limitations of Biopharmaceutics Classification System Class II and Class IV drugs. Cocrystal formation is a favoured approach for increasing apparent aqueous solubility for poorly water-soluble molecules that have no ionisable groups, and for which salt formation is not possible, or for where the physical properties of the salts formed are not desirable.  

Solvates and hydrates are well-accepted crystal forms. In many ways, a cocrystal can be thought of as a solvate, but one whose components are solid at room temperature. The cocrystal will form if the resulting crystal is thermodynamically more stable than the components. Resulting cocrystal properties are dependent upon many factors, including the starting properties of the API, the physical properties of the co-former and the mechanism by which the cocrystal is formed.  

To increase the probability of success, we [Hovione] recommend that at early-development stages to test other proven platforms, such as solid dispersions, micronised and nanosized crystals and inclusion complexes.  

: Controlling nucleation during crystallisation is an important task. What are the mechanisms for controlling crystallisation?  

 Where milling techniques can be thought of as top-down sizing techniques, controlled crystallisation is where the desired particle-size distribution is achieved from the bottom up. The objectives of a crystallisation process are twofold. On the one hand, the aim is to isolate the API in the right crystal form, typically a polymorph that provides the required level of exposure and stability. On the other hand, crystallisation may also be a purification stage, whereby the impurities remain mostly dissolved in the mother liquors.  

The kinetics of crystallisation (nucleation and crystal growth rates) are driven by the imposed supersaturation levels. The degree of supersaturation, temperature ramp, mixing, filtration and final drying process all contribute to the final particle-size distribution. Moreover, the relative importance of each factor can change at each scale.  

 What factors determine particle size? What are the differences in particle size achieved through jet-milling, wet polishing, and nanoparticle generation?  

 Particle-size reduction is not a simple phenomenon. The mechanism of generating the material of the prescribed particle size has a profound effect upon a range of physical properties that may have a significant effect on the resulting pharmaceutical behaviour. The final particle size of a material subjected to a comminution process is dictated by particle attributes, such as crystal hardness, morphology and original crystal size, as well as the size-reduction method and energy applied. Jet-milling and wet polishing may generate materials with equivalent median particle sizes; however, the resulting span from jet-milled material is likely to be wider than the wet-polished material. Amorphous material and highly reactive surfaces also may result from jet-milling while a higher level of crystallinity is maintained with wet polishing.  

Dry methods, such as jet-milling, tend to be more cost-effective (mainly because they do not require sophisticated isolating techniques), but they are more aggressive, less reproducible and more limited in terms of the achievable size reduction.  

 What factors determine which method (i.e., spray-drying, HME, spray-congealing and inclusion-complexation generation) to use to produce the amorphous solid dispersion?  

 Amorphous solid dispersions represent a tremendous opportunity for solubility enhancement of oral drugs. The resulting supersaturation levels (and hence bioavailability) and the physical stability of the final dosage form, however, depend on the manufacturing method applied. Many approaches are available to generate amorphous solid dispersions.   

Spray-drying, being a solvent method, is the most versatile technique to obtain solid dispersions due to its gentle process conditions and much wider formulation options. Spray-drying is a technology that works well in nearly every compound. Another advantage of spray-drying is that it can be effectively operated using much smaller quantities of drug substance, thereby making it the most cost-effective option during early-stage development. 

Melt methods, such as HME and spray-congealing, on the other hand, are more cost effective at the larger scale manufacturing and have the additional advantage of being solvent-free techniques. To use these methods, however, the compound needs to be soluble in the polymer/matrix and physically stable complexes need to be created. These methods are also limited to drug substances that can sustain relatively high heat loads. All these techniques are relatively well-established within the pharmaceutical industry, although spray-drying is a step ahead in terms of maturity.  

While challenging at a very small scale, the rationale design of an HME formulation is viable when the API is available in pilot-scale quantities. Where an API has low solubility in all preferred spray-drying solvents or retains extensive solvent following drying, HME may represent the best way forward for the development of a stable amorphous solid dispersion. Spray-congealing can uses a number of lipophilic excipients, which are useful in formulating poorly water-soluble compounds that will form self emulsifying drug-delivery system (SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on administration, as well as the polymers commonly used in spray-dried amorphous solid dispersions. 

Applying acoustic levitation for elucidation of amorphous material. 

Researchers at the US Department of Energy's Argonne National Laboratory have discovered a way to use sound waves to levitate individual droplets of solutions containing pharmaceuticals (1). The research facilitates the process for placing drugs from solution into an amorphous state.  

The researchers applied an acoustic levitator that uses two small speakers to generate sound waves at frequencies slightly above the audible range at approximately 22 kilohertz (1). With the proper alignment of the top and bottom speakers, the speakers create two sets of sound waves that produce a standing wave. At certain points along the standing wave, there is no net transfer of energy. The acoustic pressure from the sound waves is sufficient to overcome the effect of gravity, thereby allowing light objects to levitate when placed at these points in the standing wave (1). A video showing the technology may be found at the laboratory's website (

The technology now can produce only small quantities in an amorphous state, but it is considered a useful tool in elucidating the conditions that optimise producing amorphous material.  

Argonne National Laboratory's Technology Development & Commercialization Division is developing a patent for the method and is evaluating the technology for licensing for commercial development with pharmaceutical industry partners (1). 

Chris Benmore, an X-ray physicist at Argonne National Laboratory, led the study and teamed with various scientists for adapting the technology for drug research. These scientists include Professors Stephen Byrn and Lynne Taylor in the Department of Industrial and Physical Pharmacy in the College of Pharmacy at Purdue University (US) and Professor Jeffrey Yarger of the Department of Chemistry and Biochemistry at Arizona State University (US) and director of the university's Magnetic Resonance Research Centre. The researchers also are now working on identifying drugs most suited to applications with the acoustic levitator.  

1. J. Sagoff,  "Real-world Levitation to Inspire Better Pharmaceuticals" (Argonne National Laboratory Information, Argonne, IL [US[), Sept. 12, 2012.  

Advancing protein crystallisation: microgravity effects and predictive models. 

Elucidating the structure and sequence of proteins is an important task in understanding the biological properties of a protein and its potential as a therapeutic target. Producing a well-ordered crystal, particularly for proteins, which can be studied through crystallography, however, is not an easy task. Recent research involves examining the effects of microgravity on protein crystallisation and a computational model for protein elucidation.  

Protein crystallisation and microgravity effects

The Centre for the Advancement of Science in Space (CASIS), manager of the International Space Station (ISS) US National Laboratory, is collaborating with Merck & Co. to conduct research on protein crystallisation on board the ISS in 2013. The research will examine the effect on protein crystallisation using microgravity. 

In July, CASIS announced its first request for proposals (RFP) focused on advancing protein crystallisation using microgravity. Additionally, in early September 2012, CASIS announced an RFP focused on materials testing in the extreme environment of space. Proposals for this RFP will be accepted until 24 Oct. 2012. The final agreement with Merck is dependent on approval by CASIS' evaluation and prioritisation process, a requirement for all ISS projects. If approved, the research will begin in mid-2013. 

"We at Merck are excited to work with CASIS and explore the microgravity effects on several bioprocessing applications within the unique environment of the ISS National Lab," said Paul Reichert, chemistry research fellow at Merck Research Laboratories, in a September CASIS press release.  

CASIS is the nonprofit organisation promoting and managing research on board the ISS US National Laboratory, which includes a solicitation for proposals in relation to advancing protein crystallisation using microgravity. The RFP seeks to identify projects within the field of crystallography that CASIS will support through grant funding, facilitation of service provider partnerships, and flight coordination to and from the ISS. Crystallography is the technique used to determine three-dimensional structures of protein molecules. Protein crystallisation, when performed in space, may produce large, better-organised crystals, thereby allowing for more focused drug development. CASIS believes that its RFP will lead to the production of better crystals in the microgravity environment than can be grown on Earth.  

"CASIS has evaluated research performed to date in the life sciences and believes it is time to formally test the promising hypothesis that microgravity may produce greater internal order in protein-crystal growth," said CASIS acting Chief Scientist Timothy Yeatman, in a 26-June 2012, CASIS press release. "This could potentially lead to sharper resolution of crystals and their cognate proteins, which could produce more effective drugs for cancer and other debilitating human diseases." 

In 2005, the US Congress designated the US portion of the ISS as the nation's newest national laboratory to maximise its use for improving life on Earth, promoting collaboration among diverse users, and advancing science, technology, engineering and mathematics education. The laboratory environment is available for use by other US government agencies and by academic and private institutions to provide access to the permanent microgravity setting, vantage point in low-earth orbit and varied environments of space. 

Computational approaches for protein elucidation

Determining the structure and sequence of proteins is an important part of understanding the protein's biological properties and potential utility as a drug. Designing predetermined crystal structures, however, can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallisation (1). Researchers at the University of Pennsylvania recently reported on a computational approach for the design or proteins that self-assemble in three dimensions to yield macroscopic crystals (1).  

"People have designed crystals out of smaller, much less complex molecules than proteins, but protein design is much more subtle," said Jeffrey G Saven, associate professor of chemistry and biological and theoretical physical chemistry at the University of Pennsylvania, in a university press release. Saven conducted the research and recently reported on its results (1). Protein crystals are attractive as a nano-scale building material because their properties, particularly their exterior surfaces, are highly customisable, according to the university release.  

The researchers targeted a crystal built using a relatively small protein containing a sequence of 26 amino acid positions. The researchers assigned specific amino acids to eight of the positions, but with 18 different types of amino acid to choose from for each of the remaining 18 slots, the algorithm addressed well more than 10

  potential combinations. The researchers accounted for other characteristics, such as the spacing between proteins and their orientation with respect to one another, increasing the variables being considered, according to the release.  

"We worked on synthesising both of those steps, doing the characterisation of structure and the sequence at the same time," said Saven said in the university release. "As we move through this process, we eliminate things that will never work, such as proteins where atoms overlap in space or where amino acids don't fit into a given site. At the same time, we identify proteins that, as you vary the structure, are likely to yield a crystal." 

Specifically, the research used a three-helix coiled-coil protein designed 

 to form a polar, layered, three-dimensional crystal having the P6 space group, which had a "honeycomb-like" structure and hexameric channels that spanned the crystal (1). The approach involved creating an ensemble of crystalline structures consistent with the targeted symmetry, characterising this ensemble to identify "designable" structures from minima in the sequence–structure energy landscape and designing sequences for these structures, and experimentally characterising candidate proteins. This approach to crystal design has potential applications to the 

 design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.  

The target crystal the researchers produced is a proof of concept. "There's still much we don't know about the interactions that govern crystallisation," Saven said, in the university release. "With this technique, we can explore what those interactions are or how we might take an existing protein and engineer those interactions so we get much better structures." 

Ingredients

The physical form of an API is an important consideration in formulation development. Particle-engineering technologies, such as crystal design for controlling crystallisation and producing cocrystals, particle-size reduction and amorphous solid dispersions, help to optimise delivery of a drug.

Seeking Solutions in Solid-State Chemistry

To fulfil its duties, EMA works closely with several European organisations, including the European Commission, the European Parliament, the Council and Presidency of the EU and numerous national bodies in individual member states. EMA also cooperates with decentralised agencies of the EU, such as the European Centre for Disease Prevention and Control, the European Food Safety Authority, the European Environmental Agency and the European Monitoring Centre for Drugs and Drug Addiction. In recent years, however, EMA has placed a growing emphasis on collaborating with international pharmaceutical regulators in areas such as inspections, safety of medicines and exchange of information on issues of mutual concern (1, 2). This focus is to ensure a more global approach for the manufacture and supervision of medicinal products in the long term.  

EMA's collaboration with the US FDA tends to receive the most media attention, but the European regulator has also been increasingly interacting with its counterparts in Japan at the Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceutical and Medical Devices Agency (PMDA). 

Growing collaboration with Japan boosts drug applications and reviews

The Japanese regulators have been very committed to improving their relationship with both EMA and FDA following criticism from the pharmaceutical industry regarding a perceived time lag in Japan in the approval of new drugs and medical devices compared with the EU and the US (3). These perceptions have led some manufacturers to delay their submissions to Japanese regulators. For example, applications for an estimated 69 new active substances were submitted between 2002 and 2011 to regulators in the US, EU and Japan. Approximately 77% of these were submitted to PMDA more than one year after submission to EMA or FDA (4). Japanese regulators seem to have realised that it is imperative they improve their international standing.  

Confidentiality agreements between EMA and its Japanese partners have been in place since 2007, and were recently extended for a further year in July 2012. Such agreements facilitate the exchange of confidential information between the agencies as part of their regulatory and scientific processes. Shared information may include advance drafts of legislation and regulatory guidance documents, as well as non-public information related to ensuring the quality, safety and efficacy of medicinal products. EMA personnel also meet regularly with their counterparts from the MHLW and the PMDA.  

In November 2009, Japan sent a Liaison Official to EMA's offices as a pilot exercise. In July 2012, a report was published by EMA concerning the progress in collaboration that had been made since the appointment (5). The Japanese representative meets weekly with EMA's International Liaison Officer to discuss ongoing activities and areas that need to be addressed. Interactions facilitated by Japan's representative have covered a number of different specialist areas, including advanced therapy medicinal products, pharmacogenomics and biomarkers, paediatrics, orphan drugs and nanomedicines (5–7).  

It was concluded that the placement of the Japanese representative at the EMA has been extremely beneficial in terms of education, proactively raising awareness of possibilities for collaboration and the general timeliness of inter-agency communication. Although the EMA has not yet appointed a Liaison Officer to PMDA or MHLW, such a move seems likely in the future.  

Cooperation between Europe and Japan has been particularly beneficial in the area of advanced therapy medicinal products. Staff from PDMA attended EMA's Committee on Advanced Therapies (CAT) Workshop on Stem-cell based Therapies, followed by the CAT plenary, in May 2010, and provided input from their perspective on a draft reflection paper on stem cell-based medicinal products. Since then, PDMA has proposed additional collaboration in the area of cell therapy (5). Through a joint EU–FDA–PMDA regulatory mechanism, PMDA has also participated in scientific advice regarding renal toxicity biomarkers. 

Rare diseases have also seen much interest from both regulators. MHLW sent an external expert to EMA as part of a visiting expert programme between September 2010 and March 2011 (5). The representative was embedded in the Orphan Medicines Section of EMA and provided information to EMA's Scientific Committees and staff members. This initiative has led to better information exchange between the agencies on the outcomes of orphan medicine designations in each region (7). It has also focused attention on practical measures, such as the provision of information from the Japanese regulator in English. Regular telephone conferences are now held, usually on a quarterly basis, to discuss orphan drug topics. 

Long-standing relationships continue with US and others

EMA's most long-standing and well-documented relationship is with the FDA, with which it has had confidentiality arrangements in place since 2003. These arrangements became effective for an indefinite amount of time in September 2010. The increases in interactions between the two agencies have been driven by the Transatlantic Administrative Simplification Action Plan, which was established in 2007 to remove the administrative burden involved in interactions between regulators in Europe and the US (8). The initial plan outlined several projects, including collaborations on inspections (including in third countries), combating counterfeit medicines, safety reporting from clinical trials, exchange of information regarding policies to promote innovation in drug development, the development of biomarkers and joint agency validation of these with respect to product development and recommendations for advanced therapy medicinal products. An additional boost to cooperation was the appointment of a permanent representative from FDA to EMA's office in London in 2009. In 2010, the EMA followed suit with a permanent representative at FDA. One of the most recent initiatives was launched in January 2012 to share work on inspections of manufacturing sites in each other's territories. The general approach will use information exchange for sites and will generally focus on sites that are known to both agencies and that have a history of satisfactory GMP compliance (9). 

In addition to the US, EMA also has long-standing agreements with partner regulatory bodies in Canada, Switzerland, Australia and New Zealand, and supports the European Commission's collaboration on pharmaceuticals with China, India and Russia. In 2010, EMA and the Chinese State Food and Drug Authority (SFDA) also agreed to cooperate on GMP and GCP inspections. In addition, EMA provides SFDA with support for training and capacity building activities at their request.  

Another important partner for EMA is the World Health Organisation (WHO), with whom it works on projects concerning medicines intended for markets outside of the EU, the quality of medicines and the development of international non-proprietary names (INNs). EMA provides support to WHO to assist in capacity building for regulatory bodies in emerging markets, and also participated in the WHO's "make medicines child size" initiative, which first launched in December 2007 (10). Few essential medicines exist in child-size dosage forms and there is often insufficient information about the paediatric use of such medicines. The EMA-backed initiative has identified certain research, development, regulatory, legislative and supply gaps that need to be addressed to ensure that children receive appropriate medicines, at the right dose and with enough supportive information for the prescriber. The priority areas for the initiative are HIV/AIDS, malaria, pneumonia, tuberculosis and diarrhoea.  

In India, EMA works with regulators for the application of international standards in manufacturing and clinical trial activities with Indian regulators are invited to the agency's annual good-clinical-practice (GCP) inspector training. Indian regulators are under considerable domestic pressure to improve clinical trial standards in the country. In 2011, it was estimated that there were 438 deaths associated with clinical trials (11). Indian regulators have been attempting to strengthen their clinical trial regulations as a result, but critics continue to argue that their efforts are insufficient (11). Because many of the clinical trials in India have foreign sponsors, including some of the world's major pharmaceutical companies, Indian regulators are seeking advice from EMA and other bodies with long-standing experience in the field.  

The EMA's work with Russia is part of the European Commission's existing arrangements with the country in the area of pharmaceuticals. In 2007, a dedicated EU–Russia regulatory dialogue subgroup on pharmaceuticals was launched and the EMA gets involved when there are scientific or technical issues to discuss. 

Looking forward, EMA says that it views international cooperation as a core activity (2). Its current international strategy aims to improve communication and create synergies through collaboration with its partner regulators (2). Important international activities, in particular, include forming mutual-recognition agreements (MRAs) and other complementary arrangements. 

As drug development occurs in an international environment, regulatory agencies must collaborate and there is renewed focus on such interactions through dedicated strategies formalising the processes involved. Regulators in all regions are also under increased pressure to improve their performance, but as public bodies they have limited resources at their disposal. Another reason, therefore, for the interest in regulatory collaboration is the ability to learn from the experiences of counterpart agencies, as well as avoiding duplication of work and facilitating synergic activities. 

3. K. Tadano, "PMDA's International Strategic Plan and its Implementation" (PMDA website), 

4. Centre for Innovation in Regulatory Science (CIRS) website, "May 2012 Slide of the Month," 

5. EMA website, "Report on interactions between the Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA)," 

6. Y. Hayashi, "EU, USA and Japan (II)– Reports from Regulators on Exchange Assignments" (PMDA website), 

7. EMA website, "European Union — Japan orphan medicines cooperation". 

8. EC website, "Medicines Regulation: Transatlantic Administrative Simplification Action Plan," 

9. EMA website, "Enhancing GMP Inspection Cooperation Between the EMA and FDA," 

10. WHO website, "Essential medicines for children". 

11. E. Silverman, "Clinical Trial Deaths In India Dropped" (Pharmalot website, 2012), 

Industry Insider

EMA has been increasing its interactions with other regulatory agencies across the globe. The agency's most talked about collaboration is with FDA, but EMA has also been intently focused on bolstering its relationship with its counterparts in Japan, India and Russia.

EMA Focuses on Greater International Collaboration

Issue PDF

Click the title above to open the Pharmaceutical Technology Europe October 2012 issue in an interactive PDF format.

Pharmaceutical Technology Europe-10-01-2012

Outsourcing Pharmaceutical Infrastructure Operations

Seeking Solutions in Solid-State Chemistry

EMA Focuses on Greater International Collaboration

Pharmaceutical Technology Europe, October 2012 Issue (PDF)