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

Sean Milmo

The European Union has been given a leadership role in a   World Health Organization (WHO) pilot project on the sharing by regulatory authorities across the world of assessment   work on the marketing approval of generic medicines. It is a move that has been welcomed by European generic-drug manufacturers, but it is also a move that will highlight the EU’s own difficulties in establishing a harmonized, collaborative approval system for generic drugs among its 28 member states, as well as two other non-EU European states--Norway and Iceland--who comply with the EU licensing system. It will also throw the spotlight on the slow progress in achieving widespread use in Europe of the active substance master file (ASMF) scheme, which would speed up the quality and safety assessment of active ingredients.

The three-year pilot project, which is part of the WHO’s two-year-old International Generic Drug Regulators Pilot (IGDRP) to promote international convergence in generic-drug regulation, aims to provide a model for a permanent system among regulators for sharing work and information on the assessment of generics. Within the pilot scheme, the EU will share with non-EU regulators its assessment reports on the approval of generic drugs within its decentralized licensing procedure, which accounts for the vast majority of marketing authorizations of generic medicines in Europe. The scheme is being led by the EU’s Coordination Group for Mutual Recognition and Decentralized Procedure-Human (CMDh), which runs the decentralized system on behalf of the national medicines agencies.

“(We) strongly support the International Generic Drug Regulators Pilot,” Beata Stepniewska, deputy director general and head of regulatory affairs at the European Generic Medicines Association (EGA), Brussels, told

. “[The pilot will] enable cooperation between regulators and the industry to increase efficiency while maintaining the highest level standards based on the EU regulatory procedure,” she added.

In addition to the EU, the scheme will also initially involve Australia, Canada, Taiwan, and Switzerland, whose medicines agencies are members of the Heads of Agency Consortium. This consortium already has a generics working group that has been drawing up work-sharing arrangements in the approval of generic medicines. Other members of the IGDRP, including Russia, Brazil, China, Japan, Korea, Mexico, New Zealand, Singapore, and South Africa, may join the pilot scheme later.

“The EU leadership is a quite natural (choice), due to its long experience of managing marketing authorization procedures involving multiple partners,” said Stepniewska. “The decentralized procedure, introduced 10 years ago, was a significant improvement, although there are still some areas that can be improved (further).”


The impetus behind the IGDRP program, which includes EU involvement in exploring work sharing in ASMF activities and inspection of bioequivalence and bioanalytical operations, comes from the need to ease the burden on regulatory agencies dealing with an increasing number of generic-drug applications.

“Regulatory authorities must now also contend with more sophisticated generic-drug products and complex global production and distribution chains,” said Mike Ward, international programs manager, Health Canada’s therapeutics products directorate, in an article on the pilot project (1)

The EU’s decentralized procedure gives generic-drug companies the option of gaining marketing approval for their products in individual member states. They can also obtain authorization in groups of countries under a mutual recognition process under which approval in one country is accepted by the licensing agencies in other states.

The procedure has been a pioneer in work sharing of assessments. “One of the key elements of the decentralized procedures is the concept of work sharing between member states receiving the same application for a marketing authorization,” a spokesperson for the CMDh told 

. “As such, the elements identified by the IGDRP, like using resources for an already-assessed application, are in this way not an issue for the individual member states of the EU as the concept of work sharing is already working well.”

There are, however, problem areas where more uniformity in approaches is needed. These areas include measuring of bioequivalence, the contents of the summary of product characteristics (SmPCs), which should be consistent with the product information on the reference medicine, and dealing with information updates, especially resulting from process variations.


Generic-drug companies also have the option of having their products approved through the EU centralized approval system run by the European Medicines Agency (EMA). The EMA also arbitrates on disagreements within the CMDh on mutual recognitions and gives scientific opinions on 
assessment issues arising from the decentralized process.

There has been a sharp drop, however, in numbers of marketing applications for generic drugs through the centralized process mainly because of restrictions on duplicates or more than one authorization for a drug. The decline has stemmed from a decision four years ago by the European Commission to tighten the rules for centralized approvals in the interest of “transparency and predictability” (2).

The restrictions, which came into effect in 2011, were mainly aimed at large international generic-drug companies wanting to market drugs with, for example, different names, variations in excipients, and fewer indications. The Commission allowed duplicate applications from companies with the same ownership but placed restrictions on, for example, the use of different drug names, manufacturing sites, and excipients. Now the number of generic-drug and hybrid-drug applications under the centralized system has dropped by more than half since the restrictions were introduced. In 2013, they totalled 20 against 45 in 2011.

“[The Commission’s action] effectively reduced the interest of generic companies to use the centralized procedure,” explained Stepniewska. “(It) does not reflect how generic companies operate in the EU 28 national markets. This is really not satisfactory for generic manufacturers, as a lot of them would love to use the centralized procedure, especially in view of significant amount of reference products authorized centrally.”

Ironically, the international generic-drug companies that would like to make more use of the centralized procedure are also those most supportive of the IGDRP initiative, because it also has the potential for providing a means for gaining accelerated access to more markets.


An important tool for speeding up the assessment process is the use of ASMFs, which enable the valuable know-how of the manufacturer of the active substance to be protected. At the same time, it allows the applicant or marketing authorization holder to take full responsibility for the medicine, including the quality of the active ingredient.

An ASMF is divided into two parts--an ‘open’ part for the applicant that does not contain any confidential information and a ‘closed’ section detailing the intellectual property on the manufacturing process, which provides the basis for the regulatory authority’s assessment of the API’s quality and safety.

Since the publication of the EMA’s first guideline on the ASMF procedure in 2005 (3), the pharmaceutical industry, particularly generic-drug producers, has had difficulties grasping the ASMF process. The section on the ASMF in an EMA question-and-answer document (4) has had to be revised a number of times so that it now extends to seven pages with nine subchapters. With respect to international information sharing, the EU’S ASMF guideline poses problems. Unlike with the other active ingredient drug master file systems, the EU’s ASMF excludes excipients.

The EU has also not yet finalized its own procedure for work sharing of ASMF assessments. At the moment, the same ASMF can be assessed by different EU member states, which can result in duplication of work. This duplication can result in “inefficient use of assessor resources and inconsistent decisions being made on the same date,” according to a statement by the EMA/CMDh Working Group on Active Substance Master File Procedures (5).

 The working group was established in 2011 to set up a work-sharing system through a harmonized use of ASMF assessments. “The experience gained by the joint working group will certainly be of benefit to the IGDRP pilot,” an EMA official told 

. In 2013, the working group announced it was launching its own pilot scheme with the objective of rolling out a work-sharing procedure through a stepwise approach. The aim was to begin with a “new ASMF” covering an active substance that had not been assessed. It would extend through the whole lifecycle of the API, in particular its updates derived from variations in processes, which has been a big complication for holders of ASMFs for the generic-drug market.

A challenge for this pilot scheme and, above all, for the major IGDRP EU-led pilot project is that they both require pharmaceutical companies to volunteer to take part in them. The success of the initiative to set up a permanent international information and work-sharing model will depend on the support of the industry right from the beginning.

“Regarding the IGDRP project itself, it is too early to assess how many companies will be interested in participation,” said Stepniewska. “The level of interest may not be even visible at the beginning as the regulatory strategy for [imminent] applications has already been established and may not be easily changeable.”

28 (1) (2014). 
  2.	European Commission communication ENT/F/2/RSR re:  Handling of Duplicate Marketing Authorization Applications (Brussels, March 2010).
  3.	EMA, CPMP/QWP/227/02 

Guideline of Active Substance   Master File Procedure

 (London, April 2005).
  4.	EMA, EMA/339324/2007 

Pre-authorization Procedural Advice for Users of the Centralized Procedure

 (London, 2007).
  5.	EMA, EMA/252320/2011 

Mandate of the Working Group on   Active Substance Master File Procedures


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

Articles

The European Union takes the lead in a global pilot project on the marketing approval of generic medicines, highlighting the challenges of achieving consensus among different nations.

WHO Promotes International Collaboration for Generic Drug Approvals

Regulatory agencies in Europe are working to harmonize the marketing approval pathway of generic medicines.

Harmonizing Marketing Approval of Generic Drugs in Europe

Pharmacovigilance controls are becoming firmly embedded in the European Union’s post-authorisation regulatory system with the European Medicines Agency (EMA) acting as the pivot for an EU-wide network of agencies monitoring medicines throughout their market lifespan. The new pharmacovigilance activities stemming from the EU legislation (1-3), the first stage of which was approved four years ago, relate mainly to the reporting of adverse drug reactions (ADRs) for the detection  of safety and efficacy defects. They also cover quality problems such as deficiencies in manufacturing, inadequacies in formulations, including excipients, as well as faulty drug-delivery technologies.

EMA claims that the new pharmacovigilance legislation, implemented in mid-2012 in both the EU and the two non-EU countries of Norway and Iceland, has “brought about the biggest change to the legal framework for human medicines” in Europe since the creation of the central agency itself in 1995 (4). EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has already “made great strides towards a new era in protecting public health,” according to its chair June Raine (4). Nevertheless, as the pharmacovigilance infrastructure gradually becomes more entrenched in Europe, drug manufacturers and other marketing authorization holders (MAHs) are complaining that they are shouldering an unfair proportion of its high costs.

  Pharmacovigilance can be particularly expensive for developers and producers of biologics and biosimilars that are making up a growing proportion of new market entrants, while being   burdened with a more rigorous post-authorization regime than that for small-molecule medicines. Producers of genericmedicines are also unhappy. With a growing share of the EU market due to patent expiration of blockbuster drugs and a decline in new chemical entities, generic-drug manufacturers are having to carry a larger burden of the costs and fees for pharmacovigilance initiatives.

“It is vital that costs associated with regulatory processes do not become a barrier to developing and improving generics and biosimilar products or even to maintaining the product in the market,” said Beata Stepniewska, deputy director general of the European Generic Medicines Association (EGA), with reference to pharmacovigilance and other new legislation, at a recent regulatory affairs conference (5).

While stressing their support for an effective pharmacovigilance system to ensure patient safety, leading European pharmaceutical trade associations protested earlier this year about the lack of “proportionality and transparency” in the fees mechanism for paying EMA for pharmacovigilance activities. In a joint press release (6), the associations, including the European Federation of Pharmaceutical Industries and Associations (EFPIA), EGA and the European Association of Bio-Industries (EuropaBio), claimed that prior to the adoption of the pharmacovigilance legislation, the European Commission had been expecting annual savings of €145 million. Instead, the financial burden of the legislation on the industry has been increasing. Given that the mission of EMA and the regulatory agencies or National Competent Authorities (NCAs) in the EU’s 28 member states is to safeguard public health, the pharmacovigilance costs to industry should be partly covered by public-sector funds, the associations argued.

The industry has been pressing the commission for a dialogue on the issue that would aim to establish a fees system based on the principles of fairness and cost-effectiveness. Instead, the commission has been stressing its belief that the fees are both justifiable and transparent. A preamble to an EU regulation, published in June 2014 on the latest set of fees for pharmacovigilance work by EMA on behalf of NCAs, states that fees should be at a level that “avoids deficit and a significant accumulation of surplus and should be revised when this is not the case” (7).

Some types of medicines and MAH groups are benefiting from lower fees. Generic medicines are subject to reduced fees because of their well-established safety profiles. Small- and medium-sized enterprises (SMEs) are paying less as well.

For pharmacovigilance work by EMA on centrally approved products and to ensure harmonization of safety standards on medicines licensed by the member states, fees are fixed by EU regulation. The member states themselves set the fees for pharmacovigilance activities that are entirely the responsibility of the NCAs. At the EMA level, fees are incurred for individual pharmacovigilance procedures that can affect some MAHs more than others and are imposed annually to pay for functions that are considered to benefit all authorisation holders, such as the running of the Eudravigilance database (8) for information on all ADRs.


  There are three main procedures. Periodic safety reports (PSURs) are risk-benefit medicine evaluations submitted at stipulated intervals by MAHs. Post-authorization safety studies (PASS)characterize safety hazards or the effectiveness of risk management activities. The third is referrals to resolve concerns about the benefit-risk balance of individual medicines or combinations of them and disagreements among member states.

Under the latest set of published fees for pharmacovigilance work on products licensed under the decentralised procedure, a basic €19,500 will be charged per PSUR. The basic fee for a PASS will be €43,000 per medicine. The most expensive item is dealing with referrals for which €179,000 will be levied for assessments of one drug or combinations of two medicines, with additional combination substances costing €38,800 each. The total fee for the procedure is limited to €295,400. The annual fee to help pay for databases and monitoring operations will be €67 per active substance and for each of its various pharmaceutical forms. The set of fees confirms claims that in unusual cases, the total costs of fees could exceed €250,000 per product (8).

The EGA has estimated that an average-sized generic-medicines company could pay up to €20 million in annual pharmacovigilance fees because its large portfolio of active substances will provide the basis for a variety of authorised medicinal products (9). On top of the expenditure on fees, pharmaceutical companies will be incurring the additional administrative and managerial costs of extra market surveillance, gathering data, maintaining records and other requirements of the pharmacovigilance legislation.

From June 2014, MAHs have been required to start a process, to be completed by the end of the year of updating and improving the quality of information on authorized medicines (10). The updating will be a permanent obligation on authorization holders so that consistent information on all medicines licensed centrally and decentrally in the EU--estimated to total over 400,000 products--are available for pharmacovigilance analysis.

A major responsibility of MAHs is the continuous monitoring of pharmacovigilance data for safety signals of a possible new risk from an active substance or medicinal product. These signals could come not only from ADRs but from multiple sources, including observations of manufacturing processes. The more effectively an MAH manages signals detection, the less expensive it will be to correct deficiencies when there are signs of adverse events like manufacturing faults.

Increasing pharmacovigilance responsibilities


Over the next few years, pharmaceutical companies will see their pharmacovigilance responsibilities gradually being extended because the full implementation of the new rules will take time. At the beginning of 2014, measures introduced by the legislation such as monitoring of scientific literature, public hearings, PSUR assessment by EMA of nationally approved products were not being carried out because of the lack of fees to fund them (4).

Certain grey areas have to be clarified, such as the extent to which pharmacovigilance responsibility extends to the avoidance of medicine shortages. The scope of pharmacovigilance is, however, becoming clearer in some areas, such as formulations. An increasing number of relatively long established medicines are being reviewed by PRAC because of concerns about their formulations resulting from post-authorisation surveillance.

In July, PRAC recommended the market suspension of oral methadone products containing high molecular weight povidone, a polyvinylpyrrolidone polymer excipient (11). This suspension was due to the risk of opioid-dependent patients causing themselves serious harm from the povidone by injecting the medicine. The committee’s decision was reached after reviewing ADRs data from published literature and consulting experts.

Pharmacovigilance procedures are also likely to result in more ADRs being linked to weaknesses in manufacturing processes. With some biosimilars, the pharmacovigilance rules are particularly strict because of the possibility that adverse effects could be directly related to the manufacturing process. Furthermore, they could be different to the potential side effects of the reference product.

Europe’s pharmacovigilance system is already considered to be among the most advanced in the world, but exactly how wide its scope will be could depend on how successful the regulators and the industry are in coming to a long-term agreement on the funding of it.

Amending Pharmacovigilance Directive 2001/83

 (Brussels, December 2010). 
  2. 	EU Regulation 1235/2010 

Amending, as regards pharmacovigilance of medicinal products for human use, Regulation 726/2004 

(Brussels, December 2010). 
  3. 	Commission Implementing Regulation 520/2012 

On performance of pharmacovigilance activities

 (Brussels, June 2012).
  4. 	EMA Annual Report 2013 (London, April 2014).
  5.	EGA, “Austerity must prompt strategic regulatory rethink for generic medicines industry,” Press Release, Jan. 23, 2014.
  6.	EFPIA, EGA, EuropaBio, Association of the European Self-Medication Industry (AESGP), European Confederation of 
  Pharmaceutical Entrepreneurs (EUCOPE). “The European healthcare industry calls for balanced and transparent funding of the EU pharmacovigilance system,” Press Release, Feb. 21, 2014.
  7.	EU Regulation 658/2014. 

On fees payable to the European Medicines Agency for pharmacovigilance activities

. (Brussels, May 2014).
  8.	EU Regulation 658/2014. Annex, Part I, II, III & IV.
  9.	EGA, “Pharmacovigilance fees unjustifiably high,” Press   Release, Sept. 14, 2012.
  10.	EMA, “Companies now required to update, complete and improve quality of information on authorized medicines submitted to the European Medicines Agency,” Press Release, June 16, 2014.
  11.		EMA, “PRAC recommends suspension and reformulation of oral methadone solutions containing high molecular weight povidone,” Press Release, July 11, 2014. 

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

As the pharmacovigilance infrastructure becomes more entrenched in Europe, drug manufacturers are beginning to feel the burden of its high cost.

Extending the Scope of Pharmacovigilance Comes at a Price

European regulation of pharmaceuticals has, since the foundation of the European Union around 60 years ago, been a story of medicines being controlled in a collaboration between regulators at the EU and national levels. In recent years, this collaboration has been extended to involve not just the regulators themselves but also other stakeholders such as large, medium and small pharmaceutical companies, prescribers and patients. A major objective of the European pharmaceutical legislation, particularly at the EU level, has been to support the competiveness of the European pharmaceutical industry. This aim has become more urgent with the industry coming under pressure from globalisation. Over the past 40 years, Europe’s global share of new chemical entities (NCEs) has almost halved to around a third (1).


The importance of the future of Europe’s pharmaceutical sector was evident from the beginning of the EU’s legislative activity in the area. In the 1950s, thalidomide, a sedative used to treat morning sickness in pregnant women, caused limb deformities and other deficiencies in thousands of new-born babies. This tragedy resulted in EU member states bringing in a variety of regulatory controls of medicines, with many setting up their own licensing agencies. The thalidomide tragedy also prompted the EU to take a lead in introducing stricter medicines regulations across Europe both to protect public health and also to prevent a fledgling single market turning into a fragmented one, which would undermine the competiveness of the European pharmaceuticals industry. 

In 1965, the EU Council, representing member state governments, approved the Union’s first piece of legislation on pharmaceuticals (2). It defined what a “medicinal product” was, stipulated that a drug must be approved for marketing on the basis of evidence of quality, safety and efficacy and provided basic rules on testing requirements. 


Ten years later, the EU passed a second major pharmaceuticals directive (3), whose basic principles, like with other EU directives, had to be transposed into national legislation by the member states. This directive set out detailed rules for standardising testing and introduced a system of multi-state mutual recognition under which an authorisation of a medicine in one state could be automatically accepted by other EU states.

The directive also set up a Committee for Proprietary Medicinal Products (CPMP) in the European Commission, with the job of supervising the new multi-state system and giving its own opinion on medicines that had triggered disagreement between states. The creation of the CPMP was significant. Not only was it a central group of scientific experts (with access to 4000 specialists in the EU regulatory network), its members came from member states. It was to provide the basis for a future EU pharmaceutical regulatory system in which a central body and national authorities combined to form a Europe-wide network for controlling medicines.

By the late 1980s, it was clear that the multi-state scheme was not working. A Commission study (4) claimed that it was “hardly used by the pharmaceutical industry.” Only an average of five to six applications for multi-state approval were being made annually (4).

In 1987, the role of the CPMP was extended to cover high-tech medicines, especially those derived from biotechnological processes. National authorities were obliged to refer these products first to the committee for its opinion before making their own decisions on authorisation. This directive was a landmark because for the first time, a regulatory body at the EU level was being used to help stimulate the development of innovative medicines based on new technologies.

Two years later, the European Commission signalled its intention to impose a tighter grip on production standards when it issued its first guideline on good manufacturing practice (GMP). In 1991, the EU approved a directive (5) obliging all member states to “ensure that manufacturers (of medicinal products) respect the principles and guidelines of GMP.” In 2003, these GMP rules were considerably strengthened in a directive (6) with more detailed provisions on inspections and stricter requirements for manufacturers, particularly in the operation of quality management systems.

Creation of the European Medicines Agency


The EU took the major step of bringing in a centralised procedure for medicines in a 1993 directive, which would be part of a three-pronged system also comprising the decentralised schemes of mutual recognition and single-state approval. The use of the centralised arrangement was mandatory for biotechnological products and optional for medicines with new active substances. For EU legislators, the Commission and the pharmaceutical industry, the change was seen as a means to reduce the costs of approvals and to remove national trade barriers aimed at blocking competition to domestic drug companies from new technologies. To implement the centralised system, the European Agency for the Evaluation of Medicinal Products (EMEA), whose name was later changed to the European Medicines Agency (EMA), was set up.

 “Before EMA existed, small and mid-size companies from outside Europe, and from Europe itself, had to abstain from entering European markets, or to share the (marketing) rights with local companies,” Richard Bergstroem, director general of the European Federation of Pharmaceutical Industries and Associations (EFPIA), Brussels, told 

. “This illustrates the value of having one approval ‘portal’ for Europe,” he added.
At the core of the agency was the CPMP, now called the Committee for Medicinal Products for Human Use (CHMP). Its members came mainly from the member states, underlining the fact that medicines approval remained a matter for a network of licensing bodies. Medicines undergoing centralised approval are initially evaluated separately by a rapporteur and a co-rapporteur who are CHMP members and who may carry out the necessary scientific work in their national agencies. Once the CHMP recommends approval of a medicine, the final decision is taken by the Commission after advice on the matter by its Standing Committee on Medicinal Products for Human Use, which itself comprises experts from the member states.

“This strong interplay with their national counterparts typifies European agencies (like EMA),” explains Ellen Vos, professor of European Union law, Maastricht University, Netherlands (7). “They have been designed to operate as a kind of primus inter pares with the national authorities, instead of being hierarchically placed above (them).”

An EU regulation (8) was passed in 2004 that extended the scope of the procedure. In addition to biotech products, all orphan medicines and those drugs with new active substances for treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorder or diabetes had to be submitted to centralised approval. Optional access to the centralised system was also extended to non-innovative products, in particular generic and over-the-counter medicines. The 2004 regulation provided a platform for later expansions in the scope both of EU pharmaceuticals legislation and also of the activities of EMA. 

EMA’s functions have been extended by a series of new EU laws and other regulatory initiatives. One of the most significant of these was the 2012 legislation (9) on pharmacovigilance, which strengthened EMA’s position in the post-authorisation monitoring. As a result, it is now more involved in the supervision of the full lifecycle of drugs. Rules on post-authorisation variations in medicines have also been made stricter with clarification of which variations, such as changes to production processes, need a complete scientific assessment. 

Due to the Falsified Medicines Directive (FMD) (10), which came into force early last year, both EMA and national agencies have had to step up measures to vet the GMP standards of imported APIs, which account for 70% of the European market for active substances. A big new challenge for EMA is the increasing influence of the national health technology assessment bodies (HTAs), which now have their own European network (EUnetHTA). They assess the cost effectiveness of medicines to help governments decide whether and by how much to reimburse them under their publicly funded healthcare systems. The agency sees the necessity for close collaboration with HTAs as part of its work on ensuring patients have access to new medicines. “A strong interaction between regulators and HTAs is critical to enable innovation to reach patients, and ultimately for the benefit of public health,” says Guido Rasi, EMA’s director.

EMA is even more active in ensuring that it keeps up with scientific advances in an effort to ensure it can stimulate rather than hold back innovation. With biosimilars, Europe is now a leader globally. To a large extent, this is due to the availability of a regulatory framework, which first started to be put in place more than 10 years ago. Since then, EMA has issued more than 20 guidelines on or related to biosimilars.

“The current challenge is to make sure the development pathways--guidelines, approval mechanisms, market access procedures--are ready for the latest scientific development,” said Bergstroem. “How will the next generation of products be developed and approved? To answer this question, regulators are part of the solution.”

Medicines regulation in Europe has become not just a matter of evaluating, approving and monitoring the safety of medicines but also of encouraging innovations in medicines and their production processes to meet patients’ needs. 

A vision towards a life science strategy for Europe

, accessed 16 July 2014.
  2. 	EC Directive 1965/65, P

rovisions laid down by law, Regulation or Administrative Action relating to proprietary medicinal products

 (Brussels, January 1965).
  3. 	EC Directive 1975/318, 

Laws of Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products

 (Brussels, May 1975).
  4. 	European Commission, 

Report from the Commission on the activities of the Committee for Proprietary Medicinal Products 

(Brussels, March 1988).
  5. 	EC Directive 1991/356, 

Principles and guidelines of good manufacturing practice for medicinal products for human use

 (Brussels, June 1991).
  6. 	EC Directive 2003/94, 

Principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

 (Brussels, October 2003).
  7. 	E. Vos, 

EU Agencies: Features, Framework and Future, Maastricht Faculty of Law Working Paper

 No. 2013-3, September 2013. 
  8. 	EC Regulation 726/2004, 

Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency

 (Brussel, March 2004). 
  9. 	EU Regulation 520/2012, 

Performance of pharmacovigilance activities

 (Brussels, June 2012). 
  10. 	EC Directive 2011/62, P

revention of the entry into the legal supply chain of falsified medicinal products


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

The European Union has developed a system for evaluating, approving and monitoring the safety of medicines that has also encouraged innovation.

Collaboration and Innovation in European Medicine Regulation

Pressure is mounting on European legislators to introduce tighter regulations at both the European Union (EU) and national levels on the potentially harmful impact of pharmaceuticals on the environment. Politicians, environmentalists and even medicines regulators are calling for action in the face of increasing evidence that pharmaceutical chemicals used through the whole lifecycle of medicines from production through to disposal are posing a bigger than previously anticipated threat to the environment.

There are, however, divided opinions on what needs to be done. Some groups want stricter regulation of production processes, more consideration of environmental issues when market authorisations are granted and more rigorous rules on disposal of pharmaceuticals. Some regulators, environmentalists and fine-chemical producers support suggestions that tougher environmental standards should be applied to imported APIs. This increase in standards could be done by extending rules on GMPs to environmental protection. Others, particularly most parts of the pharmaceutical industry, believe that voluntary initiatives should be sufficient to eliminate the dangers of medicines in the environment.

The European Federation of Pharmaceutical Industries and Associations (EFPIA), representing research-based companies, concedes that the public wants more information about the risks from concentrations of certain medicines in the environment. “We believe that voluntary initiatives might be a relatively fast and flexible way (of dealing with this issue),” says an EFPIA spokesperson.


  The European Commission appears to be taking its time on the issue. The Commission is expected to release shortly a study it has funded on the environmental risks of pharmaceuticals after its publication was postponed last year (1). In 2015, the Commission is scheduled to issue a strategy document outlining ideas for new regulatory measures after which it will have the option to draw up a draft legislation.

Some countries may not wait for specific proposals by the European Commission. Instead they could enact their own regulatory schemes. This effort could happen among groups of states. Countries bordering the Rhine have, for example, already put forward ideas for international regulations to protect the river from pollutants such as pharmaceuticals.

The countries most concerned about pharmaceutical environmental threats are the Scandinavian states, Germany and its German-speaking neighbours. Sweden has been particularly active in lobbying other EU states for new EU regulations to ensure all risks associated with environmentally harmful chemicals are controlled at their source. “This should also, as far as possible, be a principle underpinning the management of environmentally harmful chemicals in medicinal products for human use,” claimed the Swedish Environment Ministry in a policy communication last year.

The Swedish government has also been taking a global perspective on environmental standards in the pharmaceuticals sector. It first proposed several years ago that the EU should move to extend the scope of GMPs to cover environmental protection in the production outside Europe of both finished medicines and APIs. 


  A lot of the latest research in Europe on the dangers of some pharmaceuticals, including APIs, to the environment has been done in Germany. With the encouragement of Germany’s Environment Ministry (BUMB), the country’s environment agency (UBA) has been conducting or funding studies in areas such as the contamination by pharmaceuticals of soil and sludge through emissions from production processes, sewage and waste-water treatment plants.

In research funded jointly by the UBA and BUMB, IWW Water Centre at Duisberg-Essen University found in an extensive literature investigation a total of 123,761 incidents of measured environmental concentrations (MECs) of pharmaceuticals across the world, according to the results of the study revealed at a workshop in Geneva in April (2). The majority of these were in concentrations in sewage, waste-water treatment effluent and surface water. Only a small minority were found in soil, sediment and slurry.

Altogether, 559 different pharmaceuticals or their derivatives such as metabolites were found in waste-water treatment influent, effluent and sludge, according to IWW. Another 38 different pharmaceuticals were found in surface, ground and drinking waters. The greatest concentration tended to be in Europe and North America. Among the 16 pharmaceuticals most frequently detected in surface, ground and drinking waters, the majority were in Europe, headed by the analgesic diclofenac and the anti-epileptic carbamazepine. With diclofenac, for example, 36 of the 50 detections were in Europe, most of which were in Western Europe.

“Urban waste water discharge is the dominant emission pathway, while discharge from manufacturing, animal husbandry and aquaculture are important regionally,” Tim aus der Beek, a senior IWW researcher told the Geneva meeting on pharmaceuticals in the environment, jointly organised by UBA and the United Nations Environment Programme (UNEP). He indicated that the problem of pharmaceutical pollution might be even more extensive because of the limitations of instrumental analytics. “The methods available are only [applicable to] some of the thousands of pharmaceuticals manufactured,” he said.


  The need to deal with the hazardous effects of pharmaceuticals is highlighted in last year’s EU priority substances directive (3). The preamble to the legislation states, “the contamination of water and soil with pharmaceutical residues is an emerging environmental concern.”

The directive stipulates that after conducting a study on the environmental risks of medicines and drawing up a strategy on how to deal with water pollution by pharmaceuticals, the Commission shall by September 2017 propose measures on their possible environmental impact. These measures, however, would be applied only “where appropriate” and could, therefore, be introduced only at the national level.

Some experts reckon that the phraseology in the directive is so vague that the Commission could avoid taking legislative steps. “A sharper formulation of the text would have been preferable,” Ake Wennmalm of the Swedish-based consultancy SustainPharma told 

“On the other hand, so many international initiatives on how to manage pharmaceutical pollution to the environment have been taken recently that DG SANCO (the Commission’s directorate responsible for health and consumer protection) sooner or later has to wake up and realise that they have been overhauled by the reality.”

If the Commission fails to act, there is a danger that certain member states will do it alone. The Swedish government, for example, has set itself targets for a non-toxic environment by 2020. “Concentrations of non-naturally occurring substances will be close to zero and their impacts on human health and on ecosystems will be negligible,” Jerker Forssel, deputy director of the chemicals division of Sweden’s environment ministry, told the Geneva meeting (4). For the moment, however, Sweden is hoping that regulatory initiatives will be taken at the EU, particularly so that risks can, as much as possible, be tackled at source.

“Environmental risks should be factored into the assessment of the benefits and risks of medicinal products,” Forssel said. “There should be a regulatory instrument at the EU level setting minimum requirements for production conditions for the authorised sales of products on the EU market.” The European Medicines Agency (EMA), as well as national agencies, should have environmental databases on substances. “The pharmaceutical authorities should be in a better position to make a first scientific estimation of risks, particularly with regard to degradability, bioaccumulation and long-term environmental effects,” Forssel said.

EFPIA has put forward a broad scheme for environmental protection including greater controls on manufacturing effluents across the industry and an expansion of the system of environmental risk assessment (ERA) applied to new medicines when they are considered for authorisation. ERAs would be extended to the whole lifecycle of a product and to long-established medicines that had not been subject to any environmental assessment, according to EFPIA. 

The Innovative Medicines Initiative (IMI), a public-private scheme jointly funded by the EU and EFPIA, has just embarked on a four-year Ecorisk Prediction (ERP) project on the development of ecotoxicological risk assessments based on knowledge from modes of action derived from preclinical and clinical studies. This project will be used in particular for predictions of possible hazardous properties of APIs.

“ERP will provide a validated model to support the evaluation of the ecotoxicological hazards of APIs during the early development process,” Bengt Mattson, co-chair of EFPIA’s task force on pharmaceuticals in the environment, told the Geneva workshop (5).

Nonetheless EFPIA has concerns about environmental standards being enforced through GMP changes. “Such an initiative might divert the focus from product quality and patient safety,” says the association’s spokesperson. “We believe there are other ways, potentially better suited, to reach the same objective of protecting the environment from possible manufacturing impacts.” R&D could be directed, for example, at the development of alternative products with reduced environmental impacts.

For the industry, a major demand is that if any new environmental legislative measures are considered by the authorities to be necessary, they should be additions to existing pharmaceutical regulations. The industry does not want the responsibilities of the environmental standards of pharmaceuticals to be in the hands of agencies that do not understand how to balance the risks and benefits of medicines. 

Milestone target of increased environmental consideration in EU pharmaceutical legislation and internationally

 (Stockholm, 31 October 2013).
  2. 	T. aud der Beek, F.A. Weber, A. Bergmann,

 “Results of Global Database of Measured Environmental Concentrations (MEC),”

 presentation at Pharmaceuticals in the Environment Workshop (Geneva, 8-9 April 2014).
  3. 	European Union Directive 2008/105/EC, 

Priority Substances Directive (also known as Directive on Environmental Quality Standards)

 (Brussels, December 2008).
  4. 	J. Forssel, 

“Milestone target of increased environmental consideration in EU pharmaceutical legislation and internationally,”

 presentation at Pharmaceuticals in the Environment Workshop (Geneva, 8-9 April 2014).
  5. 	B. Mattson, 

“Pharmaceuticals in the Environment (PIE),”

 presentation at Pharmaceuticals in the Environment Workshop (Geneva, 8-9 April 2014).


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

Concern by environmentalists, regulators and manufacturers rises over the environmental impact of pharmaceuticals.

Regulating the Environmental Impact of Pharmaceuticals

With a growing proportion of APIs and finished medicines being manufactured outside Europe, tackling the problem of quality defects has become a major challenge to the region’s pharmaceuticals inspection systems. “The causes of this increase (in defects) are multifactorial,” says an official at the European Medicines Agency (EMA). “We are studying the root causes to draw general lessons from these incidents.” As a result, there has been a steady rise in the number of regulatory measures and initiatives aimed at curbing the increase in deficient products.

EMA shares the task of coordinating the monitoring and testing of the quality of APIs and finished medicines for centrally approved products with the European Directorate for the Quality of Medicines & Healthcare (EDQM), part of the Council of Europe, whose members comprise all European states including the 28 European Union countries. The 

, which was agreed upon by the agency in December but only published in March, gives priority to raising the efficiency of inspections in relation to suspected defects, as well as GMP and good pharmacovigilance practice (GVP) (1). 

One of EMA’s key objectives this year is improvements in dealing with the “causes and impact of shortages of human medicines caused by GMP non-compliance and quality defects,” according to the programme. The EDQM, which is responsible for the 

 but also runs its own inspection operations, has been tightening and updating guidelines on the testing of products. 

Because globalisation has been closely linked with the increase in product imperfections, greater international cooperation is regarded as being crucial to solving the problem. A key part of this international collaboration is the exchange and dissemination of information about inspections, which not only expand the knowledge of agencies about quality issues but also make more effective use of already stretched inspection resources.

“We actively participate in international regulatory collaboration programmes for API and finished product inspections (since) this enables the sharing of risk information and ensures the best use of inspectorate resources between trusted regulatory partners,” says a spokesperson for the UK Medicines and Healthcare Products Regulatory Agency (MHRA), London. “Continued international collaboration is a high priority for MHRA in achieving the required regulatory oversight of the global supply chain for medicines supplied to UK and EU patients.”

Statements of GMP non-compliance available to public


European agencies now follow a risk-based approach to their choice of sites and products to be inspected or tested. Manufacturers with a history of non-compliance are, therefore, most likely to be targeted. Experience has so far shown that the vast majority of manufacturers ensure their sites and products meet quality standards with only a small minority being offenders.

Now the pressure on these companies is being stepped up after EMA announced in December 2013 that it would be publishing details of breaches of GMP standards by publishing statements of GMP non-compliance. These documents are now available on the agency’s EudraGMDP database (2), which gives public access to information on GMP certification and manufacturing and import authorisations.

A list of eight non-compliance reports on the EudraGMDP website in late March lists plants in India, China, Czech Republic, Spain and France (2). The statement issued by the French Health Products Safety Agency of the non-compliance for an API site in Maharashtra, India, of Smruthi Organics, details 29 deficiencies of which two were critical and four were major (3). One of the critical defects referred to “manipulation and falsification of documents and data” in different departments of the plant.

Another non-compliance statement issued by the same agency for an API manufacturing site in Monaco, France listed 31 deficiencies, two of them critical and 12 major (4). One of the critical deficiencies covered the manufacturing and cleaning operations for 15 APIs, for which also records were missing.

Some of the latest listed non-compliance statements were for agency inspections that had followed separate inspections of the same sites by EDQM, which had subsequently withdrawn its Certification of Suitability to the Monographs of the European Pharmacopoeia (CEP) for products made at the plants. Certifications of Suitability are issued to show that the quality of individual API meets the 

Of the 32 on-site inspections subjected to EDQM inspections in 2012, 13 (41%) were found to be non-compliant with GMP standards (5). In line with its own risk-based policy for site selections, more than half of the inspections were re-inspections. Approximately 60% of companies being re-inspected were again found to be non-compliant. “This evidenced a lack of commitment to sustaining GMP by a number of companies,” says EDQM in its latest annual report (5).

In 2012, 53% of EDQM’s on-site inspections were of plants in India and 31% in China, with only 3% in Europe (5). In response to the trend towards information exchanges, another 25 sites were covered by the directorate by sharing information with inspectorates of member states and partners.


  In collaboration with EMA, EDQM runs a sampling and testing programme covering medicines approved under the EU’s centralised licensing procedure. EMA’s scientific committees choose the sample of products, the testing of which is then co-ordinated by EDQM through the pan-European network of Official Medicines Control Laboratories (OMCL). National agencies also conduct their own sampling and testing on medicines authorised under the EU’s state-based decentralised system.

“Samples are selected on the basis of risk, such as the extent of use, number of different products, manufacturing process, chemical stability and information/intelligence from across MHRA divisions,” the agency’s spokesperson told 

The vast majority of human products tested under the centralised or decentralised scheme have been found to be within specifications. Nonetheless, 16 out of 33 human medicines tested by the EMA/EDQM programme in 2012 were found to have deficiencies, mainly relating to “technical, scientific, regulatory or editorial (relating to leaflets) nature,” according to an EMA report issued in December 2013 (6). 

The results also seemed to confirm an underlying weakness in quality management among certain companies. Approximately half the total 45 samples were those that had already been tested in previous programmes, says the EDQM. The repeated inspections are consistent with a strategy of checking certain products several times during their lifecycle.

At the same time, possibly as a result of more rigorous testing, the number of defective products is likely to continue to rise. EMA has reported that in 2013, the number of reports of quality defects went up by 20% (1). In its Work Programme for 2014, the agency is expecting a smaller increase. 

Implications of new pharmacovigilance regulations


  The scope of inspections is also being expanded. There will be more coverage of human biological pharmaceuticals. Also, the amount of post-authorisation inspections will increase, particularly as a result of the implementation of new pharmacovigilance regulations. Evidence of a manufacturer being non-compliant with not just GMP but also other safety issues, such as poor quality management, can trigger inspections under the EU’s pharmacovigilance legislation. These inspections can either be ‘for-cause’ investigations to focus on particular aspects of production or other processes, or they can be ‘full-system’ inspections.

EDQM reckons that there are opportunities for more inspections by laboratories in the OMCL network doing more testing of products from outside their own countries. Currently within the decentralised system of sampling and testing of medicines, only 10% of products tested have originated from outside the country of the OMCL laboratory.

“Analysing a series of samples from other countries together with samples from one’s own national market is both cost effective and work-reducing for all the concerned OMCLs,” says the EDQM in a position paper published last year (7). 
  “This feature of the (decentralised) scheme has been underutilised to date.”

With the continued squeeze on public sector expenditure in Europe, it is unlikely that much more money will be allocated to inspection operations. Instead, better use will have to be made of existing resources.

Work Programme of the European Medicines Agency 2014

, EMA/695772/2013 (London, Mar. 2014).
  2. 	EUDRAGMDP database, 

GMP Compliance Menu, Non-compliance reports

  accessed 9 Apr. 2014.
  3. 	EUDRAGMDP database, 

Non-compliance reports—Report No. 13MPP057

, accessed 9 Apr. 2014.
  4. 	EUDRAGMDP database,

Non-compliance reports—Report No.14MPP024

Results of the sampling and testing programme for the year 2012

, EMA/INS/S&T/613387/2013 (London, Dec. 2013).
  7. 	EDQM OMCL Network of the Council of Europe, 

General Document, History, results and benefits of testing MRP/DCP products

, PA/PH/OMCL (12) 57 3R (France, July 2013).

The rising incidence of medicine defects and shortages stemming from sub-standard manufacturing is forcing Europe to give higher prominence to more effective inspections procedures.