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

Sean Milmo

The number of substandard pharmaceutical ingredients coming into the EU has increased in recent years; however, when the European Commission (EC) first revealed details of the implementation of new EU rules for GMP standards for imported APIs, both the pharmaceutical industry and regulators warned about the potential dangers of these restrictions in causing medicines shortages. The new regulation, part of the EU’s Falsified Medicines Directive (FMD), requires that imports of APIs into the EU must be accompanied with written confirmation by a national regulatory authority that the manufacturing plant complies with GMP standards. This requirement has raised concerns that the importation of a large proportion of APIs would be severely hampered as a result. And yet, six weeks after the new rules came into effect on July 2, 2013, there has been no evidence of any major upheaval in the supplies of APIs in the EU—approximately 70% of which are imported, with 60% of these imports coming from India and China.

“Currently, we have not been notified of any critical disruption of API supplies, or manufacture of medicinal products, linked to the enforcement of the new EU rules on the importation of active substances,” a spokesperson for the EC told 

. The European Federation of Pharmaceutical Industries and Associations (EFPIA), the main trade body for research-based pharmaceutical companies, also confirmed that it had not yet received any reports from its members about any immediate difficulties with imported API supplies after July 2. An EFPIA official, however, informed

l
  that “it is too early to assess properly the impact of the new system.” 
  
  


To date, four countries (i.e., US, Japan, Australia, and Switzerland, which is a non-EU country), have been excluded from the requirement for written confirmation on grounds that their regulatory and monitoring standards on GMP are equivalent to those of the EU. Several other countries, including Brazil, Mexico, Singapore, and Israel, have applied to be exempted, or to have previous refusals of exemptions reviewed, according to the EC. The regulation also enables the authorities in the EU’s 28 member states to apply various waivers when implementing the written confirmation requirement. If, for example, an API plant has already been inspected and given a GMP certification by EU inspectors, written confirmation may be considered to be unnecessary.

Nonetheless, exactly how the new rules are being applied in individual EU countries has been unclear because of delays in including the FMD regulations in national statutes. By early August, eight of the 28 member states were yet to transpose the written confirmation obligation into their laws. In other countries, the implementation date has been held back. For example, in the UK, the requirement was not in full effect until August 20. 

In most countries, the checking of whether an imported API is accompanied by a written confirmation is left to the individual pharmaceutical manufacturers. Without the confirmation, a medicine with the imported API cannot be marketed legally in the EU. “(We) will monitor compliance with the rules in relation to finished-product manufacturers as well as companies importing active substances,” explained the Danish Health and Medicines Authority in a statement on the new rules (1). “The Danish customs authorities will not check whether the import rules have been observed.” On the other hand, countries, such as Spain, are verifying compliance through import controls at their borders while Germany and the Netherlands are planning to do the same.


  Some manufacturers were quick to react to the possibility of new restrictions on imported APIs at the time when the FMD was being debated in the European Parliament and the European Council representing EU governments. They signed deals with alternative API suppliers with GMP certification, particularly those based in the EU. “In a recent survey of our members, we found that many of them had been asked by European pharmaceutical companies to become second-source suppliers of their active substances,” said Tony Scott, advisor to the European Fine Chemicals Group (EFCG), representing EU producers of APIs.

National licensing authorities have been working closely with their countries’ pharmaceutical manufacturers to pinpoint API sources that may have difficulties complying with the new EU restrictions. Risk assessments of potentially problematic active ingredients have been carried out. These assessments investigate reasons for the absence of written confirmations, levels of existing stocks of the APIs with the medicine manufacturers, and the availability of alternative products and treatments. “(We are) aware of 107 risk assessments being carried out by member states although it is highly likely that many more have been done,” says an official at the European Medicines Agency (EMA). EMA has been monitoring the implementation of the written confirmation requirement. 

On the basis of the results of the risk assessments, national authorities have been helping pharmaceutical companies to take precautionary measures. “Some API sources for UK finished-product manufacturers were (shown to be) potentially at risk,” a spokesperson for the UK Medicines and Healthcare Products Regulatory Agency (MHRA) told Pharmaceutical Technology “However, further analysis by the manufacturers showed that such risks could be mitigated, for example, by stocks being held and the use of alternatives from approved API sources. The situation is being kept under review by MHRA at a UK level and by the weekly meetings at an EU level.” 

Due to concerns about possible medicines shortages in the short to medium term, EU regulators have been prioritizing inspections of some non-approved plants outside Europe by EU GMP inspectors. “(We know) of 12 future planned inspections of sites for which no written confirmation is available although some of these inspections may ultimately not be necessary as more non-EU authorities start issuing written confirmations,” the EMA official told BioPharm International. “In addition, EMA is aware of three EU inspections that have been carried out although it is highly likely that there have been more.”


In the longer term, EU regulators are hoping that India and China, which between them have more than 900 sites exporting APIs to Europe, will establish comprehensive and reliable GMP inspection systems that will eliminate the problem of certification of exported active substances. In India, the Central Drugs Standard Control Organization (CDSCO), part of the country’s Ministry of Health and Family Welfare, has been issuing written confirmations. Details of the confirmation with names of the APIs are available on the CDSCO website. 


written confirmations this spring through the Chinese Food and Drug Administration (CFDA), which supervises GMP inspections but only in pharmaceutical plants. It has no responsibility for GMP standards in chemical plants making and exporting APIs. “China is a very big country so there are difficulties with quality standards in APIs production while there is also a need for harmonization of GMP inspections,” commented Stefan Kettelhold, lead auditor at Germany’s blue inspection body GmbH, which does a lot of auditing work in China. “The Chinese government used to concentrate on raising production standards of companies supplying the domestic market. With the new legislation, it is also focusing on GMP of API suppliers for the international market. The Chinese authorities want to see a general upgrading of standards in pharmaceuticals.”

One likely result of tougher domestic and international regulations on production standards in India and China will be a consolidation among API manufacturers. There will be fewer of them, but they will be able to ensure that their active substances are of a more consistently acceptable quality than at present.


  1. 	Danish Health and Medicines Authority, Requirements for Import of Active Substances (API)—Questions and Answers, laegemiddelstyrelsen.dk/en/feeds/~/link.aspx?_id=65B341A60E1A427BA073611579683A43&_z=z, accessed Aug. 10, 2013.


Sean Milmo is a freelance writer based in Essex, UK, seanmilmo@btconnect.com.

Articles

The aim of the European Falsified Medicines Directive is to improve the quality of imported APIs, but does the pain now outweigh the gain?

EU Raises API Standards: A Curse in Disguise?

Planned launches of generic versions of first-generation nanomedicines and the emergence of a second generation of more-complex nanotechnologies in healthcare are now becoming a big challenge for licensing agencies. Unsurprisingly, the pharmaceutical industry has its doubts about the exact regulatory requirements for approval of innovative nanosubstances in medicinal products. The uncertainties are not only confined to Europe but also other developed regions such as North America, mainly due to the gaps in knowledge about the safety of nanomedicines derived from recent advances in nanotechnologies.  

"The industry wants greater clarity among regulators, more uniform standards, and more harmonization," Beat Loeffler, chief executive of the European Foundation for Clinical Nanomedicine (CLINAM), Basel, Switzerland, told 

. "There is a feeling that the regulators do not know what they want." An annual international conference on clinical nanomedicines, organized jointly at Basel in June 2013 by CLINAM and the European Technology Platform on Nanomedicine (ETPN), called for greater consistency among regulators in dealing with new nanopharmaceutical products.  

	In Europe, the safety rules on nanosubstances in medicinal products can be particularly perplexing because in many cases, the nanotechnologies are applied to drug-delivery systems, carriers, and imaging agents. As a result, the products have been categorized as combination products or medical devices rather than medicines. In the European Union (EU), this categorization has given much more scope for the regulatory authorities of the 28 EU member states to approve nanomedicines rather than the European Medicines Agency (EMA), whose main responsibility is the approval of pharmaceuticals.  

Some national governments have been taking their own regulatory initiatives on the management of nanosubstances in medicines and other products because of the reluctance of the European Commission (EC) to tighten up EU rules in the area. Last year, after a regulatory review on controls of nanomaterials, the EC decided to leave EU legislation on nanotechnology unchanged. Instead, the EC stated that the safety of nanomaterials should be assessed on a case-by-case basis on the grounds that they are similar to normal substances in that some may be toxic and some may not. 

In an earlier recommendation, made in October 2011, the EC provided leeway for national governments to apply their own controls on nanomaterials by recommending a broad definition of "nanomaterial." A material was defined as "nano" when it contained 50% or more particles in the size range of 1–100 nm. The EC also acknowledged that because of "special circumstances" in the pharmaceutical sector, the recommendation of an upper limit of 100 nm should "not prejudice the use of the term nano when defining certain pharmaceuticals and medical devices." 

France has been among the most ambitious EU member states in introducing a new nanotechnology legislation, which came into effect in May this year, but which has, so far, not raised any significant opposition among French pharmaceutical companies. Its main requirement is that manufacturers, importers, and distributors of engineered nanosubstances make annual declarations to the French government of the amounts they are placing on the national market with details of their uses. 

"This legislation is not a hurdle and the provision for annual declaration encourages transparency, which is a desirable objective," explains Laurent Levy, chief executive of Nanobiotix, Paris, a nanomedicine company and a member of the biotechnology committee of the French Pharmaceutical Companies Association. The increase in new nanomaterial legislation at the national level in Europe is, however, causing some nanomedicine companies to see regulation as being an obstacle to innovation. 

"Small and medium enterprises (SMEs), in particular, are regarding regulation in nanotechnology as a barrier," Levy, who is also vice-chairman of the ETPN, an EU-funded research organization, said in an interview with 

. "But once they start interacting with the regulatory authorities about their new products, they become much less concerned because they are in a dialogue with the authorities during the development of their nanoproducts, and therefore, will know what is expected of them."  

Nanobiotix has been keeping in close contact with the French National Agency for the Safety of Medicines and Healthcare Products (ANMS) in the development of a nanoparticle-enhanced radiotherapy technology. In June 2013, ANMS authorized the company to start a clinical trial of the technology for the treatment of head and neck cancer. 

The Nanobiotix technology, however, is an example of disparities outside Europe in the international classification of nanomedicines. In Europe, it has been categorized as a medical device, while in the US, FDA considers it to be a drug. As a result, Nanobiotix reckons its first products will reach the market more quickly in Europe than in the US because European national authorities responsible for licensing medical devices require fewer clinical trials than with pharmaceuticals. 

"There may be a bit of a difference in the time to market between Europe and the US, but in the end, you have to meet the same regulatory requirements of demonstrating an acceptable benefit-to-risk ratio," explained Levy. 

			Meanwhile, EMA has been stepping up its efforts to ensure a consistent EU-wide approach to nanomedicines in the two areas for which it has responsibilities—pharmaceuticals and combination products, defined as devices with a predominant pharmaceutical application. So far, EMA has only evaluated 11 marketing-authorization applications for nanomedicines, of which eight have been approved and three withdrawn. This number is fewer than in some of the larger EU countries. In France, for example, 36 nanomedicines, 21 of them being drug-delivery products, have been licensed.  

EMA has recently drafted reflection papers (i.e., discussion documents on the principles underlining the risk assessment of groups of products that may provide a basis for later guidelines) on generic nanomedicines or nanosimilars. The agency is also planning reflection papers on new second-generation nanotechnologies, on which it has already published discussion documents on block-copolymer micelles and nanomedicine coatings. As a coordinator of evaluation strategies throughout the EU's network of national licensing authorities, EMA believes it is in a strong position to boost assessment standards in areas like nanomedicines.  

"The agency has access to the best available scientific expertise in Europe, which it can consult during the evaluation of the quality, safety, and efficacy of all new compounds, including nanomedicines," an EMA official told 

. "EU-wide harmonization is one goal of EMA. However, the agency's main intention is to ensure that only safe and efficacious medicines enter the EU market." 

EMA's Committee for Medicinal Products for Human Use (CHMP) has a multidisciplinary expert group on nanomedicines, which can tap into the evaluation experience among member states. The agency has also been extending its regular contacts with non-European agencies on nanomedicines. CHMP chairs regular meetings on the matter with FDA and the licensing authorities of Japan, Canada, and Australia. "There are no official recommendations from these meetings," said the EMA official. "The focus is on knowledge-sharing and finding common areas for collaboration." 

The reflective paper on block-copolymer micelles, written jointly by the agency and Japan's Ministry of Health, Labor, and Welfare (MHLW), was an idea that came out of one of the international meetings. The EMA's investigations of nanomedicines have highlighted the need for more public-sector assistance in Europe on the characterization of nanoparticles in medicinal products. The micelles reflective paper pinpointed the importance of characterization of approximately 15 properties of block-copolymer micelles and properties related to the manufacturing process and 

behavior, as well as of the chemical structure and nature of the polymer raw materials.  

The ETPN is currently exploring the idea of setting up a European Nano-Characterization Laboratory that would act as the centre of a network of characterization facilities across Europe. It would be modelled on the US National Cancer Institute's (NCI) Nanotechnology Characterization Laboratory (NCL), which has close links with FDA.  

Europe is gradually putting together an evaluation structure that should accelerate the development and commercialization of the next generation of nanomedicines. "Like with all new technologies, there have inevitably been areas of uncertainty with nanomedicines," said Levy. "But ultimately, as knowledge of the technology increases, there will be a high level of consistency and clarity in the way it is regulated across Europe." 

is a freelance writer based in Essex, UK, 

Nanomedicines have been authorized by European licensing agencies for more than 30 years but are still posing regulatory difficulties.

Seeking Harmonization in Nanomedicines Regulatory Framework

Healthcare professionals, NGOs, and politicians have been stepping up the pressure for regulatory action on the worsening problem of medicine shortages across Europe. However, drawing up and implementing regulations at both national and EU levels appear to be far more convoluted than expected. Not only are there differences among the EU governments about what needs to be done, but such differences also exist within the industry and the pharmaceutical supply chain.  

Although it is generally acknowledged that drug shortages are causing problems to health services throughout Europe, some groups tend to be more outspoken about the issue than others. At a meeting at the European Parliament in Brussels in mid-May, three European pharmacists associations called for urgent action by governments and national regulators to tackle shortages. "With evidence strongly suggesting the problem is becoming worse, doing nothing is no longer an option," said Roberto Frontini, president of the European Association of Hospital Pharmacists (EAHP).  

A recent pan-European survey by the EAHP revealed that 99% of hospital pharmacists had experienced medicine shortages in the past year while 63% reported them to be a weekly, and sometimes daily, occurrence. Among the causes of shortages listed by the pharmacists were fewer manufacturing sites in Europe, globalization, and extended supply lines due to outsourcing and low levels of contingency stocks because of financial pressures stemming from low generic-drug prices. The Pharmacy Group of the European Union (PGEU), representing more than 400,000 community pharmacists, has suggested that manufacturers and wholesalers be legally obliged to maintain minimum national stocks of certain medicines. 

Demands for tougher regulatory measures are likely to intensify if July's implementation of tighter controls on GMP standards of imported APIs triggers more shortages, as is being predicted. The controls, targeting APIs produced mainly in Asia, are being introduced under the EU's new Falsified Medicines Directive (FMD), which stipulates that from July 2, all imported APIs must be accompanied by a written confirmation from the relevant regulatory authority of the exporting country that they comply with GMP standards equivalent to those in force in the EU. "The otherwise welcome FMD may unintentionally increase the experience of medicines shortages because of the new conditions placed on the import of APIs," said Luigi Martini, immediate past president of the European Industrial Pharmacists Group (EIPG) at the May European Parliament meeting. 

Partly in response to worries about the possible impact of the stricter checks on API imports, the European Medicines Agency (EMA) set out late last year a series of proposed steps for dealing with shortages caused by manufacturing difficulties, including GMP compliance. Some of these initiatives have already been carried out or are close to being completed, including the drawing up of a catalogue of centrally approved products (CAPs) authorized by EMA, which have previously been subject to shortages. A similar exercise is being conducted at the EU state level with nationally authorized drugs (non-CAPs).  

On the issue of new controls on imported APIs, EMA is currently establishing a list of non-EU countries for which the requirement of written confirmation from the national regulatory authority on equivalent GMP standards can be waived. In the absence of a written confirmation from an API exporter, the EU may have to perform its own GMP inspections of the exporter's production site. 

"To avoid potential shortages of medicines, the agency has developed a risk-ranking methodology for centrally authorized medicines, which can be used to prioritize inspections of active-substance manufacturers in third countries," an EMA official told 

. "This methodology is applicable to centralized products and has been shared with member states that can use it or adapt it to their specific situations."  

On other specific measures for dealing with medicine shortages, EMA has been trying to thrash out a consensus among a broad range of stakeholders. On June 5, the agency held a meeting with representatives of healthcare professionals and patients on what should be the priorities. Sharp divisions on what needs to be done have been already evident within many of the EU's 28 member states on aspects like categorizing essential medicines and what should be the responsibilities of manufacturers and wholesalers in providing information on medicines availability. These differences are now beginning to appear at the EU level, particularly on issues such as what are essential medicines. 

In Germany, doctors' organizations have been urging the use of the category of "short-term indispensible" medicines for which there is no equivalent alternative. "We are not supporting the concepts of 'essential' or 'short-term indispensible' medicines being implemented on a national or on an EU level," says Dr Siegfried Throm, R&D and innovation director at the German Association of Research-based Pharmaceutical Companies (VfA). The concept cannot be applied to many patients with illnesses that cannot be treated "by a limited set of drugs," Throm stated to 

Germany is among the several EU countries that have national working groups of representatives of industry, wholesalers, pharmacists, and other supply-chain players who share voluntary information on shortages. In some states, healthcare professionals are suggesting that the provision of information should be made mandatory. Under EU legislation, manufacturers have to provide information on plant closures and temporary shutdowns as part of their legal responsibility to ensure adequate supplies of certain pharmaceuticals. Some stakeholders, however, want a requirement for a broader range of information, which might be extended to information on difficulties with raw-material supplies. 

"There is an overall lack of information for supply-chain actors about the causes and possible duration of shortages," says John Chave, PGEU secretary general. "It is time for manufacturers, wholesalers, and pharmacists to get together with the regulators in Europe and at the very least try to improve the flow of information," Chave told 

Some manufacturer groups are emphasizing that the main reasons for shortages are not so much because of manufacturing failures but due to inadequacies in the supply chain, especially at the wholesaling and retailing stages. They point to the variety of reimbursement systems among EU states that has led to big differences in medicine prices between countries. These disparities are heightened by fluctuations in exchange rates between the eurozone of 17 countries and other EU states with their own currencies, such as the pound in the UK, which is one of the few large EU pharmaceutical markets outside the euro area. 

These gaps between national prices has triggered a considerable amount of parallel trading in medicines with products manufactured to serve the needs of a country with low prices being diverted by wholesalers, many of them pharmacists with small short-line wholesaling businesses, to EU countries with higher prices. In the UK, an EU country with a high level of parallel trading, an estimated 10–15% of the country's 12,500 community pharmacists are using wholesale dealer licences (WDL) to export medicines to other EU states. 

"Parallel trading by pharmacists with wholesale dealer licences is the main cause of current shortages of branded medicines in the UK, not manufacturing problems," explains Sam Ogden, a supply-chain specialist at the Association of the British Pharmaceutical Industry (ABPI), London, to

				 "UK medicine prices are, at the moment, among the lowest in Europe so there is a big incentive for pharmacist wholesalers to divert medicines supplied to them for dispensing purposes to other European countries with higher prices." 			

Parallel trading is legal in the EU because the right to benefit from the free movement of goods underpins the Union's single internal market. As a result of it, the ABPI claims that manufacturers oversupply the UK market with their branded medicines by an average of 120–130%. Ironically, this excess supports the case put forward by the parallel traders that their activities are helping channel surplus supplies to countries with scarcities of medicines. Disagreement between different groups about issues like parallel trading merely highlights the complexities of sorting out the EU's problems with medicine shortages. 

European governments are under pressure to take regulatory action, but solving the problem of medicine shortages is not as straightforward as it seems.

EU Battles Medicine Shortages

Pharmaceutical   companies applying for marketing approval of their products in Europe   are now required to provide the region's                          regulatory authority with documented evidence   that they are using a process that consistently produces their medicines   at                          the correct specifications and quality   standards. At the moment, companies have the option of providing   regulators with the                          details of a process validation itself or of how   they intend to carry one out. However, it is likely that the   requirements                          will become more stringent with details of   process validations being demanded not only in applications for   marketing authorizations                          but also during the post-marketing phase.

"Process   validation is an evolving landscape with a strategy being used   throughout the lifetime of a product," said Brendan                          Hughes, an industry participant from   Bristol-Myers Squibb at the expert workshop on validation of   biopharmaceutical active                          substances in April at the London headquarters   of the European Medicines Agency, the European Union's central licensing   authority. 

One of the   main driving forces behind this move, which requires drug companies to   provide more information on their processes,                          is an EMA-led policy of gathering as much data   possible on the benefits risks of medicines from multiple sources   including                          their methods of manufacture. Among the new   sources of knowledge is data generated by the EU's new pharmacovigilance   legislation                          that came into effect in July 2012. The aim is   to build up an extended database on all authorized medicines, including   post-marketing                          information on possible adverse reactions and   manufacturing issues. The database complements an expanded one on   GMP—called                          EudraGMP—containing information yielded by a new   legislative requirement on GMP in the production of APIs. 

The new   legislative initiatives need to be "systematically utilized and further   integrated to deliver continuous knowledge                          generation," said Peter Arlett, EMA's head of   pharmacovigilance and risk management, and Tomas Salmonson, chair of the   committee                          for medicinal products for human use (CHMP), in a   joint article in the agency's latest annual report published in April.   They                          added that "this concept of continuous knowledge   generation is enabled by a lifecycle approach to data collection, and   improved                          scientific and regulatory methods." 

With process   validation, EMA wants to use, in particular, a lifecycle system for new   technologies being applied in the manufacture                          of advanced therapies. Last year, after detailed   process validation, it approved Glybera, a gene therapy for treatment   of                          the rare inherited disorder lipoprotein lipase,   developed by the small Dutch company UiQure. Glybera was the first gene   therapy                          to be authorized by EMA and the Western world.   Its production process is likely to be scrupulously monitored after the   product's                          launch. According to EMA, the authorization   paves "the way for approval of similarly complex medicines in the   future, as more                          gene therapies for rare diseases, personalized   medicines, and nanomedicines are on their way." 

In a draft   guideline on process validation for dosage-form medicines, issued by EMA   a year ago and currently being finalized,                          the agency said that a manufacturing process   should be validated before a product is launched on the market. However,   with                          medicines produced by well-established   technologies, details of the validation, which can be based on the   traditional validation                          method of using studies on batch production at   the pilot stage, do not have to be placed in the application dossier for   authorization.                          Instead, the data should be held at the   manufacturing site to be made available, if necessary, for inspection.   With biopharmaceuticals                          and other "non-standard method" of production as   well as specialized products such as modified-release preparation,   details                          of the validation, which should be made with   verification data at the production-scale level, should be included in   the application                          dossier. 

During the   post-authorization phase, validation is seen in the guideline as a means   of monitoring and evaluating the processes                          in a continuous manner. "It is a science- and   risk-based approach to verify and demonstrate that a process operating   within                          the predefined specified parameters consistently   produces material that meets all its critical quality attributes   (CQAs),"                          the guideline says. 

After a consultation on the draft   guideline, one key issue being decided by EMA is the scope of process   validation, which                       comprises an evaluation and verification stage. It   was generally agreed that continuous process verification (CPV) should                       be a key component of the lifecycle monitoring of   pharmaceutical manufacturing. "These concepts (with continuous process   verification)                       are new but they are acceptable approaches," said   an official at the UK's medicines and healthcare products regulatory   agency                       (MHRA). 

Under their GMP   obligations, pharmaceutical manufacturers should be regularly checking   their production processes anyway.                       "Regardless of the nature of the medicinal product,   in accordance with GMP requirements, processes, and procedures should                       periodically undergo critical re-evaluation,   including revalidation as necessary, to ensure that they remain capable   of achieving                       the intended results," said the MHRA official. 

At the EMA's expert   workshop on process validation of biopharmaceutical active substances,   the difference between continuous                       and continued evaluation was explained in the   context of GMP adherence. While continued verification is done with   interruptions,                       continuous verification is carried out without   stopping, said Kowid Ho, a member of the EMA's biologics working party   (BWP),                       which is working on a guideline for   biotechnology-derived active substances. An enabler with continued   verification is GMP                       compliance, while with continuous verification, the   enabler is quality-by-design tools such as process analytical   technology                       (PAT) and in-line and at-line controls, added Ho,   who is a biological products specialist at the French national medicines                       agency (ANSM). Hughes however, considered that a   continued process verification can include some or all of the data   sources                       used in the CPV procedure. 

One difference   between the two is that with continuous verification, the data are   included in the application filing while                       continued verification is a basis for a prospective   proposal. It may be described in the application filing but the main   purpose                       of the data from continued verification is to show   GMP compliance. The draft guideline on process validation of dosage-form                       medicines stresses the distinction between them.   Although it says that continuous process verification depends strongly   on                       compliance with GMP principles, its data are   separate from that applying to GMP matters that are dealt with by GMP   inspectors,                       the guideline says. 

CPV is also a method   that can be introduced at any time in the lifetime of a product. It can   be used to revalidate commercialized                       products as part of the existing regulated system   of post-authorization process changes, or it can be used to support an   improvement                       program throughout the remainder of a product's   lifecycle, according to the guideline. 

A key aim of CPV is   that it should not only be a means of verifying the validity of an   original process validation but also                       for achieving greater knowledge of existing and new   production methods. "It can be used when extensive process knowledge   has                       (already) been gained through commercial   manufacturing experience," said Ho. For the European regulators, the   long-term objective                       behind lifetime process validation is that medicine   manufacturers would achieve full understanding of their production   technologies.                       It marks an important addition to the ways of   ensuring that medicines meet the highest quality standards. 

A science- and risk-based approach to verify and demonstrate that a process operating within predefined specified parameters consistently produces material that meets all its critical quality attributes.

A Lifecycle Approach to Process Validation

Combination products in the European Union (EU) are currently regulated through two different arrangements. Combinations comprised solely or mainly of pharmaceutical actives are controlled by medicines agencies while those consisting predominantly of devices are approved through a fragmented national-based system based on certification by an expert organization called the Notified Bodies. However, European politicians, non-governmental organizations (NGOs), doctors, and sections of the pharmaceutical sector have been calling for the regulation of combination products to become more centralized. This approach would make it more similar to the system in the United States where FDA approves combination products whether they are pharmaceuticals or devices. 

The pressure for a more centralized approach has intensified after the European Commission proposed revisions to the existing EU legislation on medical devices, with the aim of putting more emphasis on patient safety. The Commission suggested that the European Medicines Agency (EMA) take a wider and more active responsibility for the scientific assessment of some

 diagnostic devices such as the companion diagnostic tests (CDTs). European Biopharmaceutical Enterprises (EBE) has cautiously welcomed the Commission's proposal that EMA should participate in the assessment of clinical evidence on the scientific validity of companion diagnostics. 

"The proposed involvement of EMA in the assessment of companion diagnostics could prove beneficial, provided that the regulatory obligations and research efforts to provide clinical evidence are not duplicated," says Titta Rosvall-Puplett, executive director of EBE. 

Members of the European Parliament and some NGOs want the Commission to be much tougher with devices outside the diagnostics category by proposing the introduction of premarketing authorization (PMA) of high-risk or Class III products. This relatively large group of medical devices would then have to undertake an approval procedure similar to that applied to pharmaceuticals. Some EU member states, such as France, have hinted that they might support the idea of PMA for these devices. Inevitably, EMA is seen by PMA supporters as the appropriate body to carry out premarketing approval based on data from pharmaceutical-style preclinical and clinical trials. 

"A premarketing authorization system for high-risk devices, such as that run by FDA in the US, is needed in Europe because the safety challenges for these products is similar to those for medicines, and in some cases, the hazards could be even more severe," says Monique Goyens, director general of the European Consumer Organization (BEUC). "You can stop taking a medicine if something goes wrong, but with a deficient medical device, the patient may require surgery," she continues. "EMA has the right infrastructure and experience to do the premarketing assessment work."  

The medical devices sector, led by its main trade association Eucomed, has recognized that the legislation needs to be overhauled after a number of scandals. The biggest of these scandals came to light three years ago after a leading French devices manufacturer, Poly Implant Prothese (PIP), used industrial rather than medical grade silicone for making breast implants. The industry supports the Commission's proposed introduction of higher safety and quality standards among the Notified Bodies. It also backs more stringent requirements for clinical evidence to demonstrate the efficacy of higher-grade devices.  

However, the medical devices sector is unhappy about the Commission's move to set up a central body of member state representatives—the Medical Device Co-ordinating Group (MDCG)—to conduct an additional "scrutiny" procedure on risky devices. It is even more concerned about any initiative to bring in PMA, especially if it is operated by EMA. 

"What we want is a device-specific, effective, and predictable approval system that guarantees the highest safety for patients without necessary delays, (and which is) specifically important for the highest risk class of devices," Serge Bernasconi, Eucomed's chief executive, told a European Parliament workshop on the revised legislation in February 2013. He claimed that a centralized approval system would not work for patients and the industry. He cited research conducted last year by the Boston Consulting Group (BCG) showing that devices have been approved and made available to patients in Europe at least three years before the same devices were approved in the US.  

The high-risk Class III products incorporate substances that would be classified as medical products if marketed separately but in a combination, they enhance the functioning of the device itself. This group includes intra-uterine contraceptives and devices such as the heparin-coated catheters and bone-cement containing an antibiotic. With improvements in combination technologies, the distinction between what is primarily a device or a medicine has become harder to determine. In Europe, there has been a growing number of Class III combination products in recent years, whereby the drug and device are so closely integrated that one cannot be considered to be clearly ancillary or supplementary to the other. Furthermore, the materials and active ingredients can affect the function of each other. 

"Under the present system, this interaction between the drug ingredients and the device materials is not being properly analyzed or assessed," says Goyens. "It needs to be done by an independent body with a public health mission and not by the Notified Bodies without any public health mission." 

Although EMA has not been openly touting the EU for a key role in the assessment of devices, the agency's executive director, Guido Rasi, spoke out in an interview with Reuters last year in favor of regulating devices "at the same level of science and attention as with drugs." The agency clearly wants to establish a strong position in the assessment of combination products in areas of innovative medicine, such as advanced therapies and nanomedicines in which drugs and devices are closely integrated.  

EMA's committee for advanced therapies (CAT) already has an advisory group that acts as the Notified Body for certifying devices for gene and cell therapies, and tissue engineering. Last year, the agency started issuing public assessment reports (PARs) on pharmaceutical substances combined with biological devices. The reports included details of the safety and quality of the pharmaceutical while looking at the benefits of its integration with the biologics devices such as scaffolding. 

Nonetheless, some observers doubt whether EMA has sufficient competence to assess both pharmaceuticals and devices, and the interactions between the two. "In my experience, people from pharmaceutical backgrounds can struggle with medical devices because of different approaches to the interpretation of the data," says Peter Rose, managing director of High Edge Consulting, Nottingham, England. "The device experts are much better at stepping up to the role of medicines assessment whereas with the pharmaceuticals specialist, it is the reverse." 

There may have to be a compromise by incorporating elements of both centralization and decentralization without having to bring together expertise in pharmaceuticals and devices within one organization. "Evaluators of the drug and the device need to work more closely together with a sharing of evaluation data at some stage, but the evaluators do not necessarily need to be working in the same entity," says Marielle Fournier, director of Voisin Life Sciences Consulting, London. 

Ultimately, the key decisions on the revised or recast legislation on medical devices will be taken by the European Parliament and the Council of Ministers of governments of EU member states. As the changes are unlikely to be approved until next year at the earliest, there is plenty of time for the centralizers and decentralizers to resolve their differences.  

While there are those who want combination products to be controlled by a centralized pharmaceutical-type approval system, the majority of the medical technology industry wants to retain a decentralized device-focused approach.

Should Regulation of Combination Products Become More Centralized in Europe?

Sean MilmoThe European Commission (EC) and the European Medicines Agency (EMA), have been supporting quality-by-design (QbD) concepts over the past 10 years. In 2003, EMA set up a team to back activities in process analytical technology (PAT) in the EU. The agency has seen its PAT team as a key element in the implementation of QbD by encouraging process understanding. This knowledge becomes a basis for achieving quality by ensuring pre-defined quality criteria are met through design rather than ad-hoc testing. However, EMA has not been a strong driving force behind the adoption of QbD in the EU compared with FDA in the United States. 

Recently, both EMA and the EC have experienced pressure from the pharmaceutical industry, particularly in the biopharmaceutical sector, to do more to encourage QbD. In addition, EU authorities are becoming more concerned about the increasing number of quality defects in pharmaceutical manufacturing that have been causing a rise in drug scarcities. 

The industry has been wanting to see greater use of the Q8, Q9, and Q10 guidelines of the International Conference on Harmonization (ICH), which contain most of the basic QbD principles. These guidelines cover pharmaceutical development concepts in Q8, quality risk management (QRM) in Q9, and a pharmaceutical quality system to be implemented in the different stages of a product lifecycle in Q10. 

The ICH guidelines offer pharmaceutical manufacturers the option of taking the “minimal” or traditional approach to quality assurance or an “enhanced” structured approach, which involves concepts like critical quality attributes (CQA), design space, and control strategies. 

The industry has been urging EU authorities to put more emphasis in regulations and guidelines on the enhanced attitude to quality, particularly because QbD is seen as a means for easing the regulatory burden with less need for inspections and post-approval submissions. EMA has, however, stressed that the adoption of an enhanced QbD approach by drug producers is optional rather than a requirement. 

In comments published last year on proposed changes yet to be finalized to EU regulations on approval of manufacturing variations after marketing authorization, pharmaceutical trade associations called for more accommodation of elements of the ICH guidelines in the legislation. EuropaBio, which represents both biotechnology companies and national associations in Europe, said in its comments, published in July 2012 on a proposed revised guideline on variations, that greater recognition should be given to an enhanced QbD approach. This approach would provide opportunities for “a more science- and risk-based approach” in assessing manufacturing changes. 

In a joint comment, the European Federation of Pharmaceutical Industries and Associations (EFPIA), representing original drug producers, European Biopharmaceutical Enterprises (EBE) and European Vaccine Manufacturers (EVM), urged the EC to make clear in legal text that changes within a design space did not constitute variations that need to be approved. Design space is defined as a QbD component that sets the combination of variables and process parameters providing assurance of quality. 

The pharmaceutical industry in Europe sees QbD concepts as reflecting existing practices in the sector. Introducing them in regulations and guidelines gives more emphasis to the important elements in quality assurance. 

 “The adoption of ICH Q8–10 is not introducing new requirements or expectations,” says Julie Marechal-Jamil, senior manager of quality and regulatory affairs at the European Generic Medicines Association (EGA), Brussels. “But the regulatory adoption of the guidelines is clarifying what elements are considered essential to support the pharmaceutical development section of a marketing authorization application dossier.” Nonetheless, she claimed that “many practical questions regarding implementation of QbD remain open—even for medicines originators.” 

The European Commission’s latest revision of its GMP guide, effective from Jan. 31, 2012, shows the degree to which it is responding to calls for ICH guidelines to be given greater prominence in EU rules on quality in pharmaceuticals. Chapter 1 of the guide has been changed to align it with the concepts and terminology of the ICH Q10 guideline on pharmaceutical quality systems. It makes clear that this new chapter will also apply to two existing pieces of EU legislation on the principles and guidelines of GMP—one, for medicines for human use, and other, for veterinary applications. References in the legislation to “an effective quality-assurance system” that manufacturers must establish and implement will now be taken to mean the ICH pharmaceutical quality system. “For the purposes of this chapter, these terms can be considered to be interchangeable,” states the revised guide. 

Chapter 7 of the guide on outsourced activities has also been revised to take into account the ICH Q10 guideline. The biggest change in the GMP guide is a massive extension of Annex 2 on the manufacture of biological active substances, which has been extended from five to 32 pages and from 43 sub-items to 70. 

 “The enlargement has been necessitated by the introduction of new manufacturing technologies and the increased breadth of biological medicines into areas like gene and cell therapy,” says the Commission. It is also because of the incorporation of components of the ICH guideline on QRM. “These biological principles may display inherent variability,” the new annex states. “As a result, QRM principles are particularly important for this class of materials.” The annex includes a new section on operating principles emphasizing the need for control strategies based on QRM principles to cover various key features of production processes. 

The GMP guide may have to be further updated to highlight the importance of certain aspects of ICH guidelines because of what EMA describes as “public health crises” due to disruption to drug supplies caused by manufacturing problems. In a discussion paper issued in late 2012, the agency pinpointed the need for tighter controls on outsourced manufacturing to ensure that it is GMP compliant. EMA also thought that details of the “pre-planned inclusion of failsafe manufacturing site capacity” should possibly be included in marketing authorizations. In the longer term, the agency is considering making some QbD elements mandatory rather than optional by requiring submissions by all marketing authorization holders of risk analyses of their manufacturing processes to identify weaknesses. 

EMA is also looking to collaborate with other licensing agencies outside Europe on ways to reduce drug scarcities, including the sharing of information about product-supply issues. EMA is already involved in a joint program with FDA on the parallel assessment of marketing authorization and new drug applications, which include QbD approaches. 

One key objective of the three-year program, due to end in March next year, is to ensure consistency between the EU and the US in the implementation of ICH Q8, Q9, and Q10 guidelines. Assessments of applications are being done in parallel by the two agencies after which the review teams will discuss lessons to be learned and identify knowledge gaps. The pilot scheme should increase the momentum behind the uptake of QbD principles in Europe among both regulators and pharmaceutical manufacturers as well as lead to a more uniform policy between the EU and the US in the use of QbD to tackle issues like drug shortages due to production disruptions. 

The European Union authorities are stepping up their efforts to incorporate quality-by-design principles into their regulations and guidelines.