Sean Milmo is a freelance writer based in Essex, UK.

Sean Milmo

Producers of APIs in both Europe and the United States are hoping that a European Union (EU)-US free-trade agreement would provide a platform for the creation of a system for the global monitoring of standards of GMP. The agreement aims to dismantle barriers of transatlantic trade, particularly nontariff measures (e.g., the provision of safety certificates or evidence of quality compliance) that have generated conflicting regulatory regimes. Negotiations are expected to start this year.  

A study by the Dutch consultancy, Ecorys Nederland BV based in Rotterdam, funded by the European Commission (EC), estimated that an agreement could potentially reduce trading and investment costs in pharmaceuticals by 15.3% for US companies and by 9.5% for EU companies. The pharmaceutical sector in the EU and US hopes that, with this free-trade agreement, there would be greater consistency in areas such as regulations on GMP compliance as well as quality testing of APIs and finished medicines using pharmacopoeia standards. Once in operation, the agreement is expected to provide the pharmaceutical sector on both sides of the Atlantic with the basis for a robust system for GMP inspections of API plants throughout the world. These inspections could be done initially by joint teams of inspectors from the EU and the US, together with those from other developed countries such as Japan and Australia. 

There are, however, signs that preliminary talks between EU and US officials are running into problems. The publication of a report by a high-level working group, given the task of recommending proposals to be discussed in the negotiations on the deal, has been delayed at least three times. Within the pharmaceutical sector itself, the EU has erected new nontariff barriers and taken measures considered to be inconsistent with international GMP standards, all of which are seen as possible obstacles to a successful outcome of the discussions. 

Recently, the EU has been taking steps to strengthen checks on GMP compliance of imported pharmaceuticals while extending the scope of its GMP rules. This effort is reflected in the details of the Falsified Medicines Directive (FMD), an EU legislation aimed at combating counterfeit medicines that includes provisions for closer scrutiny of API quality. For example, a controversial section of the FMD's regulations stipulates that imports of active substances into the EU must be accompanied by written confirmation from the exporter's national regulatory authority that the plant manufacturing the API complies with GMP standards equivalent to those in the EU. This requirement is due to come into effect on July 1 this year; however, some countries will be exempted from it on the grounds that they have systems in place for regulating and monitoring GMP standards that are equivalent to those in the EU.  

The US, through FDA, is one of several countries that has applied to be assessed for exemption from the need for providing written confirmations. "We do count on the EU to put every effort into completing its US assessment in a timely fashion to allow sustained US-made API importations and sustained EU-based medicines production using these imports," says Julie Marechal-Jamil, senior manager, quality and regulatory affairs at the European Generic Medicines Association (EGA), Brussels.  

The FMD also confirms the EC's intention to extend GMP to the starting materials used in the manufacturing of APIs. For example, active substance manufacturers would be required to check out claims by suppliers about the sources of their starting materials. Some European pharmaceutical companies have protested that these new rules on starting materials exceed the EC's own GMP guidelines. 

"We have big concerns with the FMD because it has the potential to be a trade barrier," says John DiLoreto, executive director of the Bulk Pharmaceuticals Task Force (BPTF) of the Society of Chemical Manufacturers and Affiliates (SOCMA), Washington, DC. "We need to get as much international harmonization as possible with GMP. The European Commission and the FDA have got to a point where there is not much distance between what they want. The EU then comes up with the FMD, which requires the FDA to be exempted from the written confirmation rule." 

The EC insists that it is not putting up new nontariff barriers or working outside the Q7 rules on GMP for APIs drawn up by the International Conference on Harmonization (ICH). "These claims are completely unsubstantiated," says a Commission spokesperson. She stressed that the introduction of equivalence regulations in the FMD, such as the written confirmation requirement, are consistent with the rules of the World Trade Organization while the EU's GMP standards remain "equivalent" to ICH Q7 standards and GMP standards of the World Health Organization (WHO). 

Joint proposals for the EU-US trade agreement by the European and US producers of APIs are focused mainly on the issue of GMP compliance. Three of the four proposals, put forward in a joint statement in Oct. 2012 by SOCMA, the European Fine Chemicals Group (EFCG), and the Active Pharmaceutical Ingredients Committee (APIC) of the European Chemical Industry Council (Cefic), deal with GMP certification, a mutual recognition agreement of GMP inspections, and regulatory assessments of process changes. The fourth proposal focuses on the need for transatlantic harmonization of pharmacopoeia to provide more impetus to the establishment of a global pharmacopeia standard. 

On the matter of GMP certification, the joint statement emphasized the necessity of reconciling FDA's system of giving manufacturing sites "certificates of pharmaceutical product" with the EU's detailed confirmation of GMP standards. With systems on reporting of process modifications, there is also a need to resolve differences between the EU and US relating to what process changes need to be reported to licensing authorities and whether they should be reported before or after the changes are implemented. With respect to a mutual recognition agreement between the EU and the US that was first discussed in the late 1980s, the three trade organizations (SOCMA, EFCG, and APIC) argued it would enable EU and US agencies to concentrate their efforts on GMP inspections in third countries. 

Even without the EU-US free-trade initiative, progress is already being made in bilateral cooperation across the Atlantic on key issues. A four-year-old joint-plant-inspection program between FDA and EMA entered a second phase last year but is still being limited to a few sites. "At least there are stakes being placed in the ground, which ought to move things forward," says Tony Scott, adviser to the EFCG. Since 1989, the European Directorate for the Quality of Medicines (EDQM), which is responsible for the European Pharmacopoeia, and its US counterpart the United States Pharmacopeia (USP) have been drawing up mutually recognized monographs on drugs. Both are participating in a scheme, launched last year by WHO, for global pharmacopoeia standards. "Out of a total of 2200 monographs, we and the USP have so far harmonized less than 100," says Susanne Keitel, EDQM secretary. "Harmonization entails a lot of hard work." 

US free-trade negotiations, the major target will be to achieve a mutual recognition agreement because of its implication for worldwide recognition of inspections. "The talks on the transatlantic trade agreement has given us an opportunity to reopen dialogue to try to achieve an EU

US mutual recognition agreement," says Scott. "If successful, it could be the first in a series to eventually cover the global pharmaceutical industry." The vision is for the global pharmaceutical industry to have a global GMP inspection system. Perhaps the EU

US free-trade deal would kick start crucial moves towards realizing it. 

is a freelance writer based in Essex, UK, 

Articles

Discussions are underway as the pharmaceutical sector calls for greater consistency in the global monitoring of GMP compliance and quality testing of APIs and finished medicines.

Europe and the United States to Negotiate a Free-Trade Agreement

The EU approved the Falsified Medicines Directive (FMD) last year in an attempt to tackle the growing problem of counterfeit medicines. In addition to combating the trade in fake pharmaceuticals, another prime objective of the legislation is to deal with the increasing amounts of substandard pharmaceutical ingredients entering the EU under the guise of unverified compliance with cGMP standards. Currently, 70% of the EU's APIs are imported according to the European Fine Chemicals Group (EFCG). 

There has been a lengthy debate about the contents of the directive in the European Parliament and the Council of Ministers, and it has become apparent that the implementation of the directive could be as difficult as its approval. Differences over some of the final details of the legislation could mean that it will not come into full operation for at least a few years because there are still disagreements over how the GMP standards on APIs should be embodied in the directive.  

FMD is scheduled to come into effect in Jan. 2013; however, the European Commission (EC), the Brussels-based EU executive, is still in the early stages of deciding on the legal status of GMP guidelines in relation to the legislation. Some EU member states are also being slow in incorporating the directive into national legislation. For example, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) was scheduled to complete, only by 19 Nov. 2012, a consultation exercise with stakeholders on how to transpose the FMD into national law. "We are working hard to make sure deadlines are met," says an MRHA official. Furthermore, groups like European producers of APIs, whose grievances about low-quality imports have helped trigger the drafting of the directive, are still complaining that the FMD is not tough enough on GMP standards for non-EU APIs. 			

The primary intention behind the directive is to establish a secure pharmaceutical supply chain with rules stipulating quality requirements extending from starting materials to the distribution and packaging of medicines. European manufacturers of generic medicines have warned that the legislation's aim to cover both counterfeit and substandard products could push up the cost of low-priced, off-patent pharmaceuticals at a time when European governments are trying to reduce healthcare costs. Because of the range of the FMD, the EC has been given the power to draw up "delegated acts" or additions to the legislation that do not have to be approved by EU legislature, but have to be adopted by member countries without any changes. These extra details cover areas such as Internet marketing and security features on medicines packaging, on which the EC has been issuing drafts in the form of concept papers for consultation.  

A key area to be covered by a delegated act is GMP rules on active ingredients. A concept paper on proposals on principles and guidelines on GMP for active substances has completed its consultation process. At the moment, the drawing up of a delegated act on the guidelines is being handled by an expert group, in which all member states are represented. "The delegated act will be adopted and published by the Commission in 2013," an EC spokesperson said. 

The paper's main suggestion is that a 2003 directive that gave legal backing to GMP guidelines on finished medicinal products should be extended to cover the EU GMP guidelines on active substances. "This approach would bring coherence in terms of the regulatory setting for both medicinal products and active substances," the EC said. "The principles and guidelines for GMP would (as a result) be the same during the manufacturing of active substances as well as medicinal products." There are, nonetheless, parts of the 2003 legislation that would not apply to the GMP guidelines on active substances; for example, marketing authorisation for the manufacturing of pharmaceuticals and responsibility for ensuring adherence to GMP standards being allocated to a specific "qualified person" within a drug company.  

The EC has proposed that the active substance guidelines would not only apply to APIs, but also to starting materials with an obligation placed on API manufacturers to ascertain that these materials are sourced from premises claimed by the supplier. In addition, the EC suggested that the delegated act on the guidelines would have to be transposed into national legislation within six months of publication so that it can be enforced within nine months. Several groups within the pharmaceutical industry have criticised the EC proposals. Some are particularly concerned that by bringing together the two sets of guidelines, the Q7 standards for API GMP drawn up by the International Conference on Harmonisation (ICH) will be undermined. ICH Q7 provides a basis for international agreement on GMP standards on active ingredients. 

The European Federation of Pharmaceutical Industries and Associations (EFPIA) said that bringing the two guidelines together would make interpretation of GMP both ambiguous and complicated. Instead, EFPIA suggested placing the active substances guidelines in a separate section in the 2003 directive or putting these guidelines into a new directive. EFPIA stated that the obligation on API manufacturers to verify the source of starting materials was unenforceable, while the European Generic Manufacturers Association (EGA) thought that it was beyond the scope of the existing EU guidelines for active substance GMP. Several groups involved in the consultation warned that adapting to the new framework would require a period of more than nine months after publication, particularly for API producers outside the EU. Some suggested that this period between publication and enforcement should be as long as two years, which could result in the FMD not being fully implemented until 2015. 

Another controversial aspect of the legislation is the need for imports of active substances into the EU to be accompanied by written confirmation from a national regulatory authority that the plant manufacturing the API complies with GMP standards equivalent to those in the EU. Proposals on this subject were brought forth by the EC in a public consultation. According to the EC, "equivalence" to EU standards is defined as adherence to ICH Q7 and the active substances GMP standards of the World Health Organisation (WHO). Under the FMD, written confirmation will have to be provided with API shipments from July next year. 

However, the EC is also planning to operate a two-tier system under which some countries will be exempted from having to provide written confirmation on the grounds that their GMP regulatory and monitoring standards are equivalent to those in the EU. To date, Switzerland, Israel, Singapore, Brazil and Australia have requested to be assessed for exemption. Earlier this year, it was widely reported in the media that India and China, which together account for approximately 80% of API imports into the EU, considered lodging a complaint with the World Trade Organisation (WTO) that the written confirmation requirement was an unfair barrier to trade. India seemed to be backtracking in September when the country's Pharmaceutical Export Promotion Council (Pharmexcil) announced that the Indian government would be shortly setting up a competent authority to certify the quality of API exports to Europe.  

In a comment on the EC's concept paper on GMP guidelines for active substance, the China State Food and Drug Administration (SFDA) said that APIs should be given the same manufacturing authorisation as the production of medicines. Furthermore, the SFDA said that the EU should launch its own compulsory GMP inspections for active substances so that it can issue its own GMP compliance documents. SFDA's line on GMP is similar to that being pursued by the EFCG. EFCG has been recently reiterating its stance that the only sustainable solution to the EU's problems with substandard imports of active substances is the mandatory inspection by EU regulatory authorities of non-EU active substance plants or by those whose competence is acknowledged through mutual recognition agreements (MRAs). "The implementation of mandatory inspections, via an MRA approach, is a relatively small price to pay to guarantee that the quality of APIs meets the EU standard," said Gian Mario Baccalini, chairman of the EFCG pharmaceutical business committee, in a recent group press conference in Madrid.  

EGA estimates the extra costs of a strict regime for vetting GMP standards for imported APIs to be as much as €1 billion ($1.27 billion). Coupled with possible shortages of active substances if Asian producers cease their exports to Europe, this factor could decide the outcome of the current discussion about the final implementation of the FMD. 

is a freelance writer based in Essex, UK, 				

The EU fine-tunes legislation for the Falsified Medicines Directive, which is due to take effect this month as part of efforts to better protect patients from counterfeits.

Falsified Medicines Directive Takes Shape in Europe

The European Union has reached an important stage in its efforts to make the region a biosimilars production center. The London-based European Medicines Agency (EMA), which licenses EU pharmaceuticals, has finalized a guideline on biosimilar monoclonal antibodies (mAbs) and is drafting another one on the key issue of quality of biosimilars (1, 2). 

Image: influx productions, photodisk, getty images			

To supplement an eight-year-old basic regulation laying down the general principles behind the introduction of biosimilars, EMA has issued a series of product-specific guidelines. These cover biosimilars for insulins, somatropins, granulocyte-colony stimulating factor (G-CSF), epoetins, low-molecular weight heparin, and interferon-α (3). However, the guideline on mAbs is seen as technically the most challenging because of the complexity of the drugs in terms of their biological structure, range of clinical indications, and potential for unwelcome adverse effects, particularly immunogenicity.  

The mAb guideline was published at the same time as a separate one specifically on immunogenicity in mAbs, which the EMA points out are known to be associated with unwanted immunogenicity (4). Because the mAb guideline concentrates primarily on safety and efficacy, quality matters are being covered by the general quality guideline for biosimilars, currently in the consultation stage. 

"The finalization of the EU mAbs guideline can be regarded as another major milestone in the scientific framework for biosimilars," says Suzanne Kox, senior director of scientific affairs, at the European Generic Medicines Association (EGA), which is in Brussels. 

The EMA, unlike with nationally-approved generic drugs, is responsible for licensing biosimilars and has so far authorized 14—two somatropins, five epoetins, and seven G-CSF filgrastims. The publication of the mAb guideline is expected to trigger a sizeable number of mAb biosimilars applications. As with previous guidelines, however, the one on mAbs confirms the expectation that biosimilars production and development will be an expensive business because of the high cost of manufacturing facilities and of conducting nonclinical and clinical trials.  

"To get started in the biosimilars business, a lot of investment is required in biopharmaceutical production facilities—probably around €300–400 million ($390–520 million)," said Andreas Barner, chairman of Boehringer Ingelheim, at an R&D conference at Ludwigshafen, Germany, earlier this year. "Even more important will be the high cost of developing biosimilars because, for the first time, nonoriginal medicines will have to be supported by large-scale clinical trials," he continued. "The sector will suit companies which already have biopharmaceutical plants and have experience of bringing original compounds to the market." 

In the EU, the cost of  regulatory compliance for biosimilars will be pushed up even further by the implementation of the EU's new rules on pharmacovigilance, which stipulate additional postlaunch monitoring of biological drugs, particularly biosimilars, and mAbs.  

"[Pharmacovigilance] is particularly important with monoclonal antibodies as these are complex molecules with complex safety profiles," says Alan Morrison, chairman of the regulatory affairs advisor committee of the UK Bioindustry Association (BIA).

The mAb guideline's overall aim is to lay down general principles for nonclinical and clinical studies on any potential differences between a biosimilar mAb and a reference mAb and how much these differences may amount to a dissimilarity between the two products. The guideline recommends a step-wise approach, with both 

 studies being conducted on a case-by-case basis. For example, comparative 

 studies would be conducted first to assess differences in binding or function, with the necessity for additional steps involving 

work being determined by the need for additional information. 

Extrapolation of clinical efficacy and safety data to other indications of the biosimilar, based on the overall evidence from the comparability exercise, would be acceptable, according to the guideline. 

In its draft guideline on quality of biosimilars, EMA states that, "it is not expected that all quality attributes (between the biosimilar and the reference product) will be identical and minor differences may be acceptable, if appropriately justified" (2). In the mAb guideline, the agency points out that assays have been developed in recent years allowing more in-depth characterization of complex proteins both at the physicochemical and functional levels. These assays have enabled more effective assessment of minor quality differences in manufacturing processes for mAbs. Nonetheless, EMA warns that "in the current state of knowledge it may be difficult to interpret the relevance of minor quality differences" when comparing a biosimilar with a reference mAb (1) . 

Regulators expect that during the postauthorization pharmacovigilance stage, unpredicted adverse results from differences in manufacturing process could be detected. Incorrect extrapolations from nonclinical or clinical data during comparability assessments could also be revealed. 

The EU's pharmacovigilance legislation, approved in 2010, simplifies reporting of adverse drug reactions and the submission of periodic safety update reports (PSURs), data from both of which will be held centrally. 

Postauthorization safety and efficacy studies can be requested from drug-licence holders by the authorities. Applicants for marketing approvals of medicines will have to submit postauthorization risk-management plans. 

For biosimilars, particularly mAbs, pharmacovigilance requirements will be tougher than for conventional medicines. "The pharmacovigilance system is an essential part of monitoring biosimilars after approval," says Morrison. "[The legislation] provides for additional monitoring for biological products, including biosimilars." 

The mAb guideline states that applicants for marketing authorization of their mAbs or other biosimilars will have to provide a "comprehensive concept" of how further postauthorization safety studies will be carried out. The safety plan will cover safety claims based on extrapolations of efficacy and safety data during the comparability exercise and occurrences of rare and particularly serious adverse effects. In addition, because adverse reactions to biosimilars could be due to defects in manufacturing processes, the products should be clearly identifiable by name and batch number, according to the mAb guideline. 

Because of the high expenditure necessary on manufacturing facilities, development, and pharmacovigilance activities, biosimilar producers are looking for ways of curbing costs. Merck Serono and Dr. Reddy's are among pharmaceutical companies that have formed an alliance in the production and development of biosimilars, mainly mAbs, to spread the risk. DSM of the Netherlands and Crucell, a Dutch subsidiary of Johnson & Johnson, have reduced the scope of Percivia, their US-based joint venture in biosimilars by ending in-house product development. 

"In order to reduce the overall development costs, we need in the EU and in the US a scientific framework which allows global development," says Kox. The European Commission has appeared to be acknowledging the need for global development of biosimilars when it recently announced it would accept applications for approvals of biosimilars containing data from reference products that come from outside the EU.  

"[With this announcement] a new regulatory paradigm is born, which is a great achievement after years of discussion," says Kox. "The issue of the reference product is not the only one to achieve global development. But for companies to be able to use data from tests from reference products that are not sourced from the EU constitutes a major and far-reaching regulatory breakthrough." 

The European Commission has yet to finalize details on how a comparability exercise with a reference product outside the EU would work. But the decision does seem to show that the EU is intent on continuing to take a lead on biosimilar regulatory matters without waiting for US guidance on the development of biosimilars to be formally adopted.  

Sean Milmo is a freelance writer based in Essex, UK, 

Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies—Non-Clinical and Clinical Issues 

Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, revision 1

 3. EMA, "Multidisciplinary: Biosimilar,"   

www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c

Guideline on Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use

The European Medicines Agency has added granularity to its biosimilars approval pathway by releasing a guideline on biosimilar monoclonal antibodies (mAbs).

EU Sets Guidelines for Biosimilar Monoclonal Antibodies

The government of Turkey is drawing up a program in coordination with the pharmaceutical industry to create ways to make the country a regional production center for pharmaceuticals serving Europe, Central Asia, and the Middle East. 

Turkey's two main pharmaceutical trade associations—Pharmaceutical Manufacturers' Association of Turkey (IEIS) and the Association of Research Based Pharmaceutical Companies (AIFD)—have been supporting the government's initiative with the publication of reports on the future of the Turkish drugs industry by two leading US-based consultants. AIFD published a report, Vision 2023, by PriceWaterhouseCoopers (PwC) in September 2012 and IEIS issued a study by the Boston Consulting Group (BCG) late last year (1, 2). 

Turkey, one of the world's fastest growing emerging economies, faces considerable challenges in achieving its aim of becoming a major global power in pharmaceuticals. Within its own market, it will have to triple the average annual growth rate and raise the annual increase of domestic production sales 12-fold, while exports will have to increase almost six times, according to PwC. 

There also needs to be a big improvement in relations between the industry and government, particularly with research-based companies, most of them multinational players. Companies have been critical of the power wielded over the sector by the Turkish Ministry of Health, which accounts for more than three quarters of drug purchases.  

Earlier this year, AIFD accused the government of not doing enough to encourage investment and being too focused on cutting drug prices. Now, as the government works on an action plan for the sector, ties between the two sides have become closer. Kadir Tepebasi, AIFD vice chairman, said in July at the BIO International Convention in Boston, "We are very happy and excited" that the government and the research-driven segment had the same long-term targets and approaches. 

Nihat Ergun, the minister of science, industry, and technology whose department is responsible for the development of the pharmaceuticals sector, has revealed that the strategy document due to be finalized by the end of this year will highlight R&D assistance, investment in human resources, and more backing for drugs exports. 

The PwC and BCG reports propose that the industry can reach ambitious targets by 2023—if the appropriate steps are taken. A substantial increase in domestic and foreign investment in the sector is required, especially in production capacity for high value-added medicines, according to PwC. BCG stresses the importance of the development of production and R&D clusters. 

Over the next 10 years, the objective of more than doubling pharmaceutical production to $23 billion, raising exports from approximately $520 million last year to approximately $7 billion, turning a current trade deficit of more than 80% into a net surplus, and increasing R&D investment from around $100 million to $1.7 million "is not just a dream," says Guldem Berkham, AIFD president.  

Both the industry and the government believe that the country has several advantages that provide a platform for the rapid growth of the pharmaceutical sector. The country's domestic-drugs market has more than doubled over the past 10 years, while with a population of 75 million, its per capita medicines consumption is still relatively low. Over the past decade, visits to primary care facilities have more than tripled and to hospitals more than doubled, according to BCG. 

Turkey has a strong infrastructure for medicines manufacture with around 300 pharmaceutical producers, making it the seventh largest pharmaceutical industry in Europe and 16

  in the world. The country has well-established universities providing a basis for R&D activities. 

Above all, Turkey is strategically located at the crossroads between Europe and Asia. It has the logistical connections to supply Europe, which has annual pharmaceutical imports of $264 billion; Russia with imports of $11 billion; Central Asia and the Caucasus with $2 billion; and the Middle East and North Africa with $14 billion. 

To realize the potential of these benefits by attracting large amounts of investment, the industry argues that the government must first introduce a more sustainable drugs-pricing policy. Currently, Turkey's medicines prices are among the lowest in the world. 

The country has had some recent investment successes. These include Amgen's $700-million takeover of Mustafa Nevzat Pharmaceuticals, a Turkish generics producer; the formation of a partnership between Otsuka of Japan and Abdi Ibrahim of Turkey; and a decision by Zentiva, a Czech subsidiary of Sanofi, to make Turkey a production base for generic drugs.  

A survey earlier this year by AIFD, however, found that price cuts by the government have been holding back investment. More than half of 23 research-based pharmaceutical companies said they had had to cancel investments because of government measures, mainly on prices. 

Another problem has been a decision by the government not to recognise GMP certificates from the EU and the US. Instead, foreign production facilities have to be inspected first by Turkish officials before Turkish marketing licences for medicines can be granted. 

An AIFD survey in April 2012 found that approvals of almost 300 medicines of foreign research-based companies were being delayed because of the lengthy time it was taking to gain GMP certification. "The GMP issue has to be sorted out through mutual recognition agreements with the EU and US," says an IEIS official.  

Another drawback for Turkey is a poor reputation for IP protection in which it is rated 70

  in the world. In some key areas, the country has a lot of ground to make up before its pharmaceutical manufacturing industry can attain a top global ranking. 

Turkey's Pharmaceutical Sector—Vision 2023 Report, Strategy Document

 Partnering with the Government to Globalize the Turkish Pharmaceutical Industry 

—Sean Milmo is a freelance writer based in Essex, UK

The government of Turkey is drawing up a program in coordination with the pharmaceutical industry to create ways to make the country a regional production center for pharmaceuticals serving Europe, Central Asia, and the Middle East.

Report from Turkey

Drug regulatory agencies in Europe are reporting, either in absolute terms or proportionately, rises in deficiencies found in pharmaceutical plants across the world during GMP inspections. The increases seem to be related to the growing number and scope of inspections, although some speculate that the expansion of manufacturing outsourcing, particularly to producers in Asia, also has something to do with it.  The most significant rise in deficiencies has been recorded by EMA, which is the centralized authority of medicines in the European Union. In its latest annual report, published in June 2012, EMA revealed that there has been a 38% increase since 2011 in quality defects. These defects are primarily tied to GMPs and other standards such as Good Clinical Practices (GCPs).  

The number of quality defects has almost doubled since 2009, going from 80 to 154 in 2011. At the same time, the number of GMP inspections have gone up from 175 to 375 over the three-year period.  Inspections have increased to more closely monitor the production of APIs and overall quality at multiproduct sites, where  manufacturers are making both finished products and drug substance, according to EMA.  

Some of the reported deficiencies have been related to "the increasing numbers of centrally authorized products (and) the inclusion of a basic compliance evaluation of printed packaging material," says an EMA official. The agency has widened the breadth of its compliance checks by including coverage of what it classifies as "minor" issues because such problems could indicate a departure from GMP. "EMA has updated and refined its standard operating procedure (SOPs) for reporting of product defects in 2009 which may be reflected in the absolute numbers of defects subsequently reported," explains a spokesperson for the Association of the British Pharmaceutical Industry (ABPI) in London.  

The association also points out that, despite the recent rise in quality defects reported by EMA, there were " fewer product recalls overall—the number of Class 1 recalls, the highest risk category of recall, went down from 14 to 2." Among national regulatory agencies in the EU, a large proportion of whose GMP inspections cover the production of generic drugs and their APIs, there are mounting worries about the rise, either in absolute terms or proportionately, of specific deficiencies. In the latest report on GMP inspections for fiscal year 2011–2012 from the UK Medicines and Healthcare products Regulatory Agency (MHRA), the proportion of "critical" deficiencies or those with a significant risk of causing harm to patients went up from 6.5% of inspections in 2010–2011 to 8.6% this past year.  

The agency now has a program directing its inspections at higher risk operations. "As a result, the focus of the inspections in general may change or for higher risk sites the inspection may target certain areas of concern," says Ian Jackson, the MHRA's operations manager and senior GMP inspector.  

The list of the agency's Top 10 GMP deficiencies for the past year was again topped by unsatisfactory investigation of anomalies in production. Other categories moving up the deficiency ranks were poor quality management, inappropriate response to complaints, substandard process validation, and unsatisfactory auditing of suppliers. Contamination appeared to be an increasing problem as well with incidents of defective control of microbial contamination doubling. Neither EMA nor MHRA are blaming the current level of GMP defects on the increase in exports of drugs and their active ingredients into the EU from countries, such as India and China.  

"There is no evidence that suggests a bias between products manufactured inside or outside the EU," says the EMA official. However, production standards in Asia and in other non-EU areas could become more of an issue next year when the region's new Falsified Medicines Directive, aimed at combating counterfeit medicines, starts to be enforced. This directive requires stepping up GMP inspections of the API production sites supplying Europe, a large proportion of which are based in Asia. National agencies within the EU have already begun to warn pharmaceutical manufacturers that they should not use active ingredients from non-GMP API manufacturers outside the EU. Starting in 2013, EU manufacturers will have to be even more vigilant about the source and quality of their supplies.  

 —Sean Milmo is a freelance writer based in Essex, UK.

EMA and MHRA provide insight into increased GMP deficiencies.

Report from Europe

With a population of 38 million, Poland has the largest pharmaceutical market in Central and Eastern Europe (CEE). But in terms of international competiveness and exports performance, its pharmaceutical industry lags behind other smaller countries in the region, like Hungary. Now the Polish pharmaceutical industry is trying to catch up on the international stage.  

But instead of focusing on chemical-based medicines, it is concentrating on biopharmaceuticals, in particular biosimilars. Poland's government wants to establish a knowledge-based economy in the country. So it sees biotechnology, in which biopharmaceuticals is the fastest growing segment in Poland, as one way of doing this.  

In academia, the country already has a number of centers of expertise in biotechnology which gives it a relatively active R&D platform in the discipline and, above all, the teaching capacity for producing a steady stream of graduates in biotechnology. The country currently has around 8000 biotech students and 1300 graduates in the subject. There are 21 university biotechnology faculties, seven of which offer doctoral studies in the discipline. The government is trying to exploit this human capital in biotechnology by offering investment grants for biotech projects on the basis of the number of jobs being created and the amount of R&D which will be conducted.  

In addition, the EU is offering financial support for biotech projects to aid development in regions like the CEE. Along with several other Eastern European countries, Poland joined the EU in 2004. Currently there are around 70 biotechnology companies in Poland, most of them in biopharmaceuticals and diagnostics, with annual revenues of around $100 million. The majority are located in emerging clusters in Warsaw, Lublin, Krakow, Wroclaw, Poznan, and Gdansk, where there are universities and research institutes specializing in life sciences and biotechnology. Most of the biopharmaceutical companies are concentrating on the discovery and development of new drugs as well as small-scale contract manufacturing. A few are dedicating themselves to the development and production of their own biopharmaceuticals, above all biosimilars.  

"Biosimilars have better prospects since Poland has a chance to specialize in this area rather than in purely innovative biotech products," says Monika Stefanczyk, head pharmaceutical market analyst at PMR Ltd., a Polish market research company.  

The three main players in the fledgling biosimilars sector are Mabion, formed five years ago by a consortium of four pharmaceutical and two research companies, Polpharma, Poland's largest domestic pharmaceutical producer, and Bioton Group, which has been active in setting up foreign partnerships. Mabion, whose R&D work at its Lodz site has been aided by EU funding, is working on several projects, mostly oncology treatments. Two are monoclonal antibody drugs which the company believes will assist it in gaining a foothold in a world market for humanized monoclonal antibodies predicted to be worth $60 billion by 2015.  

Mabion has a proprietary technology, which it claims enables it to make the drugs 30 to 40 % cheaper than conventional methods. Polpharma, which has formed a specialist unit, Polpharma Biologics, for the development and production of biological products, was scheduled to open a laboratory in the first quarter of this year in Gdansk. The laboratory includes scale-up equipment for production of clinical trial batches and a pilot plant.  

Warsaw-based Bioton signed a €55.5 million ($73 million) deal with the Icelandic generic-drug company Actavis in February for the development and manufacture of recombinant human insulin (RHI) products, which Actavis will market throughout Europe and in the US. Just how many other Polish companies join these three front-runners in biopharmaceuticals could depend on the availability of private funds to supplement public-sector finance.  

"Access to private money is a bit easier but it is still difficult to find investors willing to put money into biotechnology," says Marcin Los, chief executive of Phage Consulting, in Gdansk, which is encouraging the development of a niche bacteriophage segment in Poland. Biotechnology scientists and entrepreneurs in Polish biotechnology, including in biopharmaceuticals, claim that another barrier is proposals to tighten up the country's already restrictive legislation on genetically modified organisms (GMO).  

"Planned amendments to the regulations fail to take into account the ability of  GMO research to be carried out in labs in controlled conditions without any risks to the environment," says Professor Tomasz Twardowski, vice-president of the Polish Federation of Biotechnology. "The new rules handicap Polish biotechnology in comparison to regulatory conditions in other countries. The Polish government is responding to public opinion hostile to GMOs rather than taking note of the scientific evidence." Polish biotech companies argue that the government cannot have it both ways. It cannot expect to have a thriving biotech sector while having legislation which hampers its activities.  

Sean Milmo is a freelance  writer based in the UK.

Poland's government aims to make the Eastern European country a biotech powerhouse.