Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

Medicine regulatory agencies in the EU, US and Australia have been successfully collaborating for some time now with regards to GMP inspections of API manufacturers, but now they are seeking to further expand this international effort by looking to include additional partners. The initial pilot scheme ran from 2008 to 2010 and involved the sharing of inspection plans, reports and information concerning API manufacturers, as well as several joint inspections. The project was so successful that cooperation in these areas has continued. 

The current partners have agreed that clear criteria need to be established for any new participant to be accepted, as well as to maintain ongoing participation. To this end, the EMA has published a document entitled

 Programme to rationalise international GMP inspections of active pharmaceutical ingredients/active substances manufacturers 

that outlines the terms of reference and procedures for authorities to participate in the programme. Some of the points mentioned are that the reference GMP standard for inspections will be ICH Q7 and that participants will be responsible for ensuring that the appropriate confidentiality arrangements are in place. In addition, if an inspection results in regulatory action or license suspension, this decision will be shared with the other authorities. 

However, if a potential new partner does not meet the criteria listed in the document, they may still be accepted into the programme for the benefit of global health. In addition, nonparticipating authorities may still request access to inspections information. In this case, information sharing will be facilitated in a way that does not compromise any confidential information. 

The WHO has already agreed to become a new partner in the collaboration through its Prequalification of Medicines Programmes, which aims to make quality priority medicines available to those who need them and includes evaluation, inspection and quality monitoring activities. 

Articles

Medicine regulatory agencies in the EU, US and Australia have been successfully collaborating for some time now with regards to GMP inspections of API manufacturers, but now they are seeking to further expand this international effort by looking to include additional partners.

Greater International Collaboration

A US court has denied AstraZeneca’s request for a preliminary injunction against FDA. AstraZeneca filed a lawsuit against the agency at the beginning of March 2012 with regards to the antipsychotic medicines Seroquel (quetiapine fumarate) and Seroquel XR.

The injunction had sought to prevent FDA from granting final marketing approval to a generic version of quetiapine until December 2012. Prior to the injunction, AstraZeneca had filed Citizen Petitions with FDA last year concerning labeling issues for generic drugs. Seroquel is required to carry warnings about hyperglycemia and suicidal thoughts, but the same labeling may not be needed for generic versions of the drug. AstraZeneca’s Citizen Petitions attested that generic quetiapine should require the same warning labels and that FDA should withhold approving any generic form of the medicine that does not include such labeling.

FDA denied the petition earlier this month.

The US is not the only territory where AstraZeneca faces loss of market exclusivity for Seroquel. Last week, a court in the UK ruled that the formulation patent protecting Seroqeul XR was invalid. The patent had been challenged by several generic drug manufacturers, including Accord Healthcare, Intas Pharmaceuticals, Hexal, Sandoz, Teva UK, and Teva Pharmaceutical Industries. Teva UK launched

a generic version of Seroquel in the UK on Mar. 27, 2012.

, the core patent for Seroquel IR expired in September last year and pediatric patent is due to expire soon. Seroquel XR reportedly still has protection until 2017, but according to a 

 AstraZeneca is engaged in numerous proceedings related to the drug and its related patents and regulatory exclusivity.

Nurofen Plus Recalled; Sabotage Suspected

A US court has denied AstraZeneca's request for a preliminary injunction against the FDA.

Court Dismisses AstraZeneca's FDA Lawsuit

	The 2009 swine flu pandemic (and panic) has been forgotten by most, but regulators, global health organisations and pharmaceutical companies are continuing post-pandemic activities, which include keeping an eye on new cases of the illness and monitoring the safety of pandemic vaccines.

	This week, swine flu returned to headlines after 

 published in the Public Library of Science appeared to confirm a link between GlaxoSmithKline’s Pandemrix vaccine and cases of narcolepsy in children in Finland. Between 2002 and 2009, instances of narcolepsy were around 0.31 per 100,000 people. In 2010, this jumped to 5.3 cases per 100,000, which equates to a 17-fold increase.

	Regulators have been aware of the link for some time. In July 2011, the European Medicines Agency (EMA) 

 a safety review of Pandemrix, Although the overall risk–benefit balance of the vaccine remains positive, the EMA recommended that it should not be used in persons under 20 years of age unless a seasonal trivalent influenza vaccine is not available, or if an H1N1 vaccination is required.

	But the problem is that the link is not well understood. Pandemrix was used in dozens of countries, but the spike in narcolepsy cases only seems to be prevalent in Finland and Sweden. In Canada, an equivalent H1N1 vaccine (Arepanrix; also manufactured by GSK) was widely used, but did not seem to trigger an increase in narcolepsy cases. It is believed that Pandemrix interacted with genetic or environmental factors, which raised the risk of narcolepsy.

	According to media reports, the governments of other countries are aware of the study results and other research is taking place.

	The situation is a prime example of the importance of genetic factors on pharmaceutical products. A growing trend in the industry is for companies to explore the possibilities of personalised medicine, which involves matching the right patient with the right treatment. This is already being done for some medicines, including cancer medicines, using diagnostic tests.

	Unfortunately, Pandemrix has a long way to go before such a test can be developed, since it is still not known exactly how the vaccine is linked to narcolepsy. To complicate matters narcolepsy itself is also not very well understood. However, GSK is reported to be conducting more studies in order to further explore the link between its vaccine and narcolepsy.

The 2009 swine flu pandemic (and panic) has been forgotten by most, but regulators, global health organisations and pharmaceutical companies are continuing post-pandemic activities.

Vaccine Tied to Narcolepsy

The European Medicines Agency (EMA) has released 

 that outlines a European-wide approach for dealing with transparency and access to information included in marketing authorization applications. The guideline identifies which parts of an application dossier can or cannot be released in response to document requests.

According to the EMA, the guidance is a "major step for transparency" when dealing with requests for access to marketing authorization applications and is the first time that a harmonized, European approach to the issue has been adopted. Going forward, all regulatory authorities in the European Economic Area will apply the same principles.

The guidance limits information that regulators will consider to be commercially confidential in a marketing authorization application. Exceptions will mainly relate to information about the quality and manufacturing of a medicine, in addition to information about facilites and equipment, as well as some contractual arrangements.

Also explained in the documents is how to identify personal data relating to patients, experts or staff. Personal data will be defined by EU Directive 95/46/EC.

Two guidance documents were adopted. The first is titled titled 

HMA/EMA Guidance document of the identification of commercially confidential information information and personal data within the structure of the Marketing Authorization (MA) Application — release of information after the granting of a Marketing Authorization

Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in MA Applications

The guidance has been welcomed by EFPIA. However, in a press statement Richard Bergström added, “Despite EFPIA´s reservations, EMA has decided to also release nonclinical data (preclinical). An important consequence of the release of all this information is that we must update the concept of "regulatory data protection" (RDP), i.e that second applicants cannot refer to submitted data until after 10 years.” 

Recently, the EMA has been criticised for its perceived lack of transparency. In 2011, an article published in the British Medical Journal highlighted the difficulties in obtaining access to unpublished trial reports from the EMA. In other related incidences, access to documents was only given after intervention by the European ombudsman.

EMA plans public access to side-effects data

The European Medicines Agency has released guidance that outlines a European-wide approach for dealing with transparency and access to information included in marketing authorization applications.

Europe Adopts Transparency Guideline

The European Medicines Agency (EMA) has recommended that manufacturing processes for two anticancer medicines be transferred from Ben Venue Laboratories to alternative facilities. The decision follows GMP shortcomings identified at the US-based manufacturer in late 2011, and marks the end of the EMA’s review of all fourteen centrally authorized medicines that were produced at the site. 

Presently, Ben Venue is the only facility that manufactures the anticancer medicines Caelyx (doxorubicin hydrochloride) and Ceplene (histamine duhydrochloride) for the European Union market. While the transfer takes place, the EMA has recommended that the marketing authorizations for both medicines be maintained because they are considered essential for patients and no alternative suppliers or formulations are available. The Agency also added that no concerns have been raised from the safety monitoring of these medicines. 

 that no new patients should be started on the treatment. This recommendation will remain in place until the sterile filtration and aseptic filling processes have been transferred to a new manufacturing site, which should be completed by September 2012. Following this, Janssen-Cilag International NV, which is the marketing authorization holder, will transfer all the remaining steps in the manufacturing process to a new site by the end of 2014. 

Janssen-Cilag is also required to promptly report any safety concerns, as well as submit a monthly report detailing reports on effects that could be related to sterilization problems. 

For Ceplene, manufacturing processes must be transferred by the marketing authorization holder (EpiCept GmbH) by the end of 2013. In the meantime, the company must continue to visually inspect vials for signs of particle contamination.

The EMA’s Committee for Medicinal Products for Human Use has been reviewing medicines manufactured at Ben Venue since early November 2011 after an inspection identified problems in the company’s quality-management system, particularly in relation to the sterile filling process and possible particle contamination during manufacturing. The decisions regarding Caelyx and Ceplene mark the end of the review. For the 

 in the review, the EMA recommended that Ben Venue be removed as a manufacturing site. The review also resulted in the suspension of the marketing authorizations for the skin infection medicine Vibativ and the diagnostic agent Luminity until a suitable, alternative manufacturing site is approved.

Ben Venue Laboratories is the manufacturing arm of Bedford Laboratories, which is a Boehringer Ingelheim company.

The European Medicines Agency has recommended that manufacturing processes for two anticancer medicines be transferred from Ben Venue Laboratories to alternative facilities. The decision follows GMP shortcomings identified at the US-based manufacturer in late 2011, and marks the end of the EMA's review of all fourteen centrally authorized medicines that were produced at the site.

EMA Says Ben Venue's Anticancer Drugs Should be Manufactured in Another Facility

	GlaxoSmithKline this week gave the UK government and several trade organisations reason to celebrate after announcing that it will build a new manufacturing facility in the country - the first in almost forty years. The facility will be dedicated to biopharmaceuticals and will create new jobs in Ulveston, Cumbria, which has been chosen for the new site.

	In addition, GSK will make investments at other UK manufacturing sites in Montrose and Irvine (Scotland), Ware (Hertfordshire) and Barnard Castle (County Durham). Overall, the company will invest more than £500 million ($794 million) and create up to 1000 jobs. In a nod to the environment, some of the funding will be dedicated to environmentally friendly manufacturing technologies.

	The investments are one of the largest commitments to the UK life-sciences sector in recent years.

	Ulveston was chosen as the location for the new facility following a feasibility study that GSK conducted in 2011. Construction is estimated to cost £350 million ($555.66 million) and is anticipated to begin in 2014 or 2015. It is expected to take at least 6 years before the facility is fully operational. GSK also added that it is considering further investment at the site up to £700 million ($1.1 billion).

	The company already has a site at Ulveston that employs around 240 people and manufactures key ingredients for antibiotics.

	More than £100 million ($158.8 million) will be invested at GSK’s Montrose and Irvine sites.

	At Montrose, the investment will be used to enable the site to manufacture key materials for respiratory medicines, as well as aluminium adjuvants, which are used in vaccine manufacture. This will be the first time a UK GSK site will participate in the company’s vaccine manufacturing supply chain.

	Meanwhile at Irving, GSK will increase production capacity for antibiotics in response to demand for these medicines in emerging markets. At both sites, GSK will also invest in green energy production and environmentally friendly manufacturing technologies.

	Finally, investments totalling £80 million ($127 million) will be made at sites in Ware to increase manufacturing facility for the company’s upcoming respiratory inhalation device and at Barnard Castle to a centre of excellence for dermatology manufacturing.

	For years, stakeholders of the UK bio/pharmaceutical industry have been calling on the government to do more to encourage manufacturing investment from big pharma companies amid a fear that the country could be losing its “pharma lustre” (

read the article from our columnist Nathan Jessop

). Ironically, despite criticism, the UK has been busy launching a number if initiatives to strengthen its position in both R&D and manufacturing. Finally though, these efforts seem to be paying off. GSK’s CEO, Sir Andrew Witty, says that the UK’s patent box scheme, in particular, has been beneficial. The 

 is an initiative that will allow companies to apply for a reduced rate of corporation tax that on patented technology.

	“The introduction of the patent box has transformed the way in which we view the UK as a location for new investments, ensuring that the medicines of the future will not only be discovered, but can also continue to be made here in Britain. Consequently, we can confirm that we will build GSK’s first new UK factory for almost 40 years… We are also actively considering other investments in our UK manufacturing network which would create further jobs and reinforce the UK’s international competitiveness and as a world leader in life sciences.

	GSK announced its investments following the release of the UK government’s 2012 Budget. In the 

, UK Prime Minister David Cameron said, “This is excellent news, a major investment that will create many highly skilled jobs and provide a great boost to the economy.  It shows why we are right to cut business tax and focus on making the UK a dynamic and competitive place that can attract exactly this type of high tech investment.”

	However, although the announcement has elicited a positive response from both the UK government and industry stakeholders, including the 

Association of the British Pharmaceutical Industry 

, the UK’s largest trade union, Unite, explained that the government must still do more.  Although welcoming GSK’s investments, Unite national officer, Linda McCulloch, pointed out in a 

 that “the pharmaceutical industry has seen a lot of uncertainty with over 10,000 jobs lost in the past five years”. She added, “We need to invest in the UK’s manufacturing skills base for the future. Once again, we call on the government to invest in the UK’s manufacturing skills base with a long-term solution.”

UK Adopts Multimillion-Pound Life-Sciences Strategy

Pfizer Site Closure “Shocking Wake-Up Call” for the UK

GlaxoSmithKline this week gave the UK government and several trade organisations reason to celebrate after announcing that it will build a new manufacturing facility in the country.