Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

	The head of the Association of the British Pharmaceutical Industry has issued a stark warning about the state of the UK’s pharmaceutical industry. In particular, concerns have been raised about the lack of new medicines being used by the UK’s National Health Service (NHS), which has affected the profits of the pharmaceutical industry and led to a decline of R&D in the country.

	“The UK is amongst the slowest adopter of new medicines in Europe, despite low prices, and our spending on new medicines is actually set to decline further,” Stephen Whitehead, chief executive, said in a 

	The UK was one of the first countries to adopt a healthcare pricing reform with the establishment of the National Institute for Health and Clinical Excellence (NICE), which assesses whether a medicine should be available to patients on the NHS based on its costs versus therapeutic benefits. However, even when new medicines are approved by NICE they are not always available to NHS patients. Whitehead said, “A recent report by the NHS Information Centre found that NICE-appraised medicines are being underused by the NHS in half of disease groups.”

	The ABPI claims that there is a ‘social contract’ between the pharmaceutical industry and the NHS. Whitehead explains, “We discover and develop medicines, at great cost whilst enduring the very real risk of failures, to address unmet medical need and we get reward for that risk through sales to the NHS so we can reinvest in new treatments… This contract has broken down, new medicines are not being adopted despite stringent assessments of value.”

	With new medicines not being used, the pharmaceutical industry is not receiving sufficient return of investment. Whitehead added that R&D in the UK has declined from 6% of global clinical trials to just 1.2%. In addition, he added that job losses in the past four years within the industry have amounted to 16000.

	Healthcare systems are changing across the western world. Elsewhere in Europe, Germany is in a state of flux because of changes in the pricing environment that now require new medicines to undergo a cost–benefit analysis before they can be reimbursed.

	Across the pond in the US, the country is on the cusp of healthcare reform with the Patient Protection and the Affordable Care Act.

	Only time will tell how these reforms will impact the global pharmaceutical industry.

	In the UK, Whitehead is calling for stakeholders to address the issues at hand now. “We need to find a model that stimulates R&D, motivates the NHS to adopt innovative medicines and encourage further discoveries in our battle against disease,” he said.

	Fortunately, it’s not all doom and gloom for those of you based in the UK. The government is already aware of the problems and is looking to address them through its Innovation, Health and Wealth review, which is being supported by the ABPI. The review aims to ensure both the sustainability of the NHS and the research-based industry.

Articles

The head of the Association of the British Pharmaceutical Industry has issued a stark warning about the state of the UK’s pharmaceutical industry.

ABPI Issues Call to Improve UK Pharma

The European Commission (EC) has issued final approval for Europe’s first gene therapy-a treatment for a rare genetic disorder that currently has no other treatment options. According to a 

, the treatment is the first gene therapy to be approved by regulatory authorities in the Western world.

uniQure’s Glybera (alipogene tiparvovec) is intended for patients with lipoprotein lipase deficiency (LPLD) suffering from recurring acute pancreatitis. LPLD is an inherited disorder affecting approximately one or two people per million. Patients are unable to metabolize fat particles in the blood, leading to inflammation of the pancreas and, in some cases, early onset of diabetes and cardiovascular complications.

Using adeno-associated virus vectors as a delivery vehicle, Glybera adds working copies of the lipoprotein lipase gene into muscle cells to enable enzyme production.

“The final approval of Glybera from the EC marks a major step forward in making gene therapies available not only for LPLD but also for a large number of rare disease with a very high unmet medical need,” Jörn Aldag, CEO of uniQure, said in a statement. The company is planning to also apply for regulatory approval in the US, Canada, and other markets. In addition, the company is examining potential treatments for acute intermittent porphyria, Sanfilippo B, hemophilia B, and Parkinson’s disease in other development programs. 

The European Medicines Agency (EMA) first recommended Glybera for approval in July 2012, with the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommending the granting of a marketing authorization under “exceptional circumstances.”

uniQure first submitted Glybera as a treatment for LPLD to the EMA in 2009, but received a negative opinion. However, in early 2012, the EC asked the EMA to re-evaluate the application in a restricted group of patients with severe or multiple pancreatitis attacks.“The evaluation of this application has been a very complex process,” said an EMA 

, “but the use of Glybera in a more restricted indication than initially applied for, which targets the patient population with greatest need for treatment, and additional analyses by the Committee for Advanced Therapies have added to the robustness of the data provided and allowed the CHMP to conclude that the benefits of Glybera are greater than its known risks.”

Commercial roll out of the treatment is expected to begin in the second half of 2013. uniQure will be required to provide data from a registry set up to monitor outcomes in patients treated with Glybera, which the EMA will review as they become available.

The European Commission has issued final approval for Europe's first gene therapy-a treatment for a rare genetic disorder that currently has no other treatment options.

EC Approves Europe's First Gene Therapy

	The end of October saw chaos in the Caribbean and then on the east coast of the US, particularly in New York and New Jersey (the location of some of PharmTech’s offices) after hurricane Sandy hit.

	The pharmaceutical industry has also been affected by the storm, with several big companies delaying the announcements of their third-quarter financial results. On a consumer and patient-level, medicinal supplies have been affected in the US by looting and power outages affecting the filling of prescriptions.

	The pharmaceutical industry has been quick off the mark to lend a helping hand to relief efforts.

	Amgen and its Amgen Foundation are contributing $250 000 to support relief efforts, including $100 000 to Direct Relief International, a nonprofit support agency that provides medical assistance to people affected by poverty, disaster, and civil unrest. The remainder of the funding will mainly be disbursed to organizations that specifically support dialysis patients, who require timely treatment.

	Eli Lilly’s Lilly Foundation has donated $200 000 to the American Red Cross. In addition, the foundation is also contributing one dollar for every dollar donated by Eli Lilly employees to the American Red Cross or Salvation Army .

	Abbott is donating $1 million in funding and product donations to support relief efforts. Grants will be awarded to the American Red Cross, AmeriCares, Direct Relief International and World Vets, and product donations have also been made to Direct Relief International and Feeding America. Product donations have also been supplied to food banks and free clinics in states along the east coast of the US, including New Jersey, New York, North Carolina, South Carolina and Virginia.

	Abbott was actually already preparing for a potential disaster before Sandy struck. Earlier this year, the company worked with Feeding America and Direct Relief International to strategically preposition disaster relief packs containing nutritional and medical products in coastal communities that were seen to be at high risk of hurricanes. Abbott donated adult and paediatric nutritional products and rehydration solutions to the packs, as well as nutritional products, medicine and diabetes care products to free clinics via Direct Relief International. Food banks and free clinics can access the packs as needed to quickly respond to local needs.

	Although it’s great to see the pharmaceutical industry offering a helping hand - and even preempting disasters with prepared packs - I was a little disappointed to see that little media attention, both inside and outside of the pharmaceutical industry, has been directed at the Caribbean countries hit by the storm, some of which were hit by Sandy when it was in its Category 2 state. None of the press statements from the above companies mentioned humanitarian aid in the Caribbean, although perhaps efforts are being pursued in a quieter fashion. As more pharmaceutical companies no doubt come forward with donations and aid offering, I hope greater attention is spread across the damage caused by Sandy on a global basis.

The end of October saw chaos in the Caribbean and then on the east coast of the US.

Pharma’s Efforts in Hurricane Aid

Extractables and leachables (E&L) are a growing area of concern for regulators, necessitating more oversight from pharmaceutical manufacturers. 

 conducted an industry roundtable to find out more about how extractables and leachables are being approached in the pharmaceutical industry. Participating in the roundtable were: Piet Christiaens, scientific director at Toxikon Europe; Andrew Feilden, chemistry operations director, at Smithers Rapra; Allen Kesselring, scientific director at EAG Life Sciences; Paul Killian, analytical technology R&D manager at EMD Millipore Corp.; and Wayland Rushing, senior scientific advisor at ABC Laboratories. 

What are the most common causes and types of E&L? Are certain drug-delivery and packaging components or product types more at risk?  

 Leachables can come from any part of the supply chain or manufacturing process. Issues can arise from the container–closure system itself, the secondary packaging, the manufacturing process, and even the storage environment. Typically the longer the contact time and larger the contact surface area the higher the degree of risk of leachables. The drug-delivery systems most at risk are inhalation aerosols and injectable suspensions. As a rule of thumb, the container–closure systems for these types of products have a large elastomeric content that tends to produce more leachables. Another area of major concern for regulators is biological formulations. Even though a leachable in its own right may be safe, it may have a significant impact on the properties of a biological formulation, such as aggregation, particle formation, or other product quality issues. 

 E&L studies are traditionally associated with orally inhaled nasal drug products, ophthalmic products, and injectable products. The quick and efficient transport of material to the bloodstream, which make these drugdelivery routes highly effective, also makes them susceptible to impurities arising from the packaging (this neardirect exposure concern also extends to many topical, transdermal, and implantable products). In addition to route of delivery, exposure quantity, and length of use are other key considerations that must be evaluated during E&L testing.  

 I perform E&L studies on single-use processing equipment. The most common types of E&L are small-oxygenated compounds, such as ketones, aldehydes, and organic acids generated from the gammairradiation process. The compounds and concentration will vary based on the strength of the gamma irradiation; the higher the dose the greater the number and concentration of these compounds. Other common compounds may include breakdown products from antioxidants added to protect the plastics, siloxanes from silicone tubing, and residual solvents from filters. 

				Some drugdelivery systems are at higher risk for E&L issues. Liquid-based parenterals and inhalation products (specifically metered-dose inhalers and inhalation solutions) tend to attract the greatest regulatory scrutiny. Because of the nature of these formulations, it is not uncommon to observe leachables above the recommended safety concern thresholds set for the toxicological evaluation of leachables in final-drug products. A second common source of E&L problems we have seen at ABC Laboratories is the actual labels that are applied to the drug product bottles. The inks and glues used in labeling have been a common source of leachables in several drug-device configurations. 

				How are analytical tests today able to take a risk-based approach with E&L? What has changed in this area compared with 10 years ago? 

 To take a "riskbased" approach, it is necessary to understand what the real risk is. Several years ago, risk-based approaches were often taken solely based on a paper evaluation of the known composition of a raw material (e.g., anti-oxidants, slip agents, nucleating agents, and other processing aids) or on the results of limited extraction studies. Today, the risk of finding leachables in the drug product and the harm it can cause to the patient is much better understood. As a consequence, more emphasis is placed on the risk evaluation of actual leachable data. 

 Taking a risk-based approach to E&L has been aided by the implementation of ICH Q8, Q9, and Q10. Aspects of quality by design are also being introduced that could help reduce the overall testing burden, but these studies are very intensive at the start of an E&L project.  

It is now much easier to implement a risk-based approach to testing, but regulators are still very risk averse, so reducing the amount of testing can be challenging. Often, the risk of not carrying out the testing outweighs any associated cost or time savings that can be achieved.  

 The heightened sensitivity and widespread prevalence of mass spectroscopy as a detector for analytical techniques such as gas chromatography, liquid chromatography, and inductively coupled plasma has had big impact on E&L evaluation. While this improved technology, together with enhanced libraries (both commercially available and proprietary), allow for faster, and more efficient and accurate assessment of E&L, they have also led to a significant increase in regulatory expectations.  

 As analytical instrumentation improves, so does the ability to detect compounds at lower concentrations. In some ways, this has created new challenges with E&L studies, when it comes to identifying and quantifying small peaks observed in chromatographs. In the past, these compounds would not have been detected by the instrumentation.  

However, one currently accepted practice to address this issue is to develop an analytical evaluation threshold, which allows the chemist to disregard small peaks and to instead focus on the larger peaks. 

 A risk assessment of the known compounds used in the manufacture of the container–closure system, such as processing aids (e.g., slip agents and mold-release agents) or other additives to the product, may determine that there is no need to monitor for these compounds during the E&L program. This approach can, in some cases, significantly simplify analytical tests. However, these compounds may contain impurities or react unpredictably in the presence of the drug product formulation. As a result, care should be taken when performing these assessments to ensure they are performed using the proper data and appropriate justifications.  

During the past 10 years, we have seen significant advances in analytical technologies. Newer instrumentation can gather qualitative structure information while simultaneously meeting the low sensitivity commonly required for E&Ls and reducing the length of time required to perform toxicological assessments on observed leachables. 

				Are you seeing more trends in simulation studies to predict and prevent E&L with certain drug-packaging components, and what are the benefits?  

				There is a growing consensus that simulation studies, as suggested by the Product Quality Research Institute–Parenteral and Ophthalmic Drug Products work group, are a very relevant addition to the traditional E&L approach, typically as a step in between extraction studies and formal leachable studies (using validated methods). Filling the containers with a relevant simulant and studying the migration behavior of the pharmaceutical packaging under accelerated storage conditions will help to understand which compounds (found in the initial extractable studies) are actually leaching out of the packaging components into the drug product. In the ideal case, the drug product itself can be selected (e.g., in an accelerated leachable study using screening analyses) because this approach should not only predict the real leachables profile, but also reveal potential interactions between the leachables and the drug product. 

 Nothing can be done to prevent extractable testing at some point in the development process. However, simulation studies are being more widely used to predict if there are going to be any leachable issues before the end of the shelf life or if there are issues with the formulation. This is happening more with biological and parenteral formulations. 

				Simulants (or model solvents) are very useful in E&L studies because they reduce the matrix interference with the analytical assay and are less expensive and safer to use than actual product streams. Simulations are especially useful when evaluating new packaging material. Several candidates can be evaluated side by side, and those with the most extractables can be eliminated from consideration early in the process. 

				The performance of leachable simulation studies to predict and potentially prevent leachables is increasing. The products that would typically benefit from these studies are liquid-based formulations such as parenterals, oral solutions, and inhalation solutions.  

These studies are typically set-up by using the actual drug product formulation (or a justified simulant) to mimic a worst-case scenario interaction between the container–closure and the formulation. Accelerated conditions can be employed, but should not be overly aggressive. An aggressive extraction approach typical of a controlled extraction study can lead to dozens, if not hundreds, of observed compounds above the reporting threshold. From experience, we know that most of these compounds are unlikely to extract under typical storage conditions. Traditionally, determining which compounds would actually leach required performing stability studies on the actual drug product, but this approach can be time-consuming and costly, especially when evaluating multiple container–closure configurations.  

Simulation studies allow for better decision making process during the development program. As a result of the study design of simulation studies, the compounds observed are more likely to be representative of the compounds that that can be expected to leach. By using these data, we can make decisions on which packaging may result in overall leachable levels and which methodologies will likely need to be employed to monitor for actual leachables in the drug product. 

				What are the current regulatory expectations (for example among FDA and EMA) for E&L testing and removal?  

 Ten years ago, there was a general consensus that leachables were a subset of the list of extractables that could be detected in a properly designed extractable study. FDA and EMA guidance documents issued based on this assumption placed much emphasis on performing risk evaluations on extractable results. However, a better understanding on the interactions of drug products and packaging materials has made it clear that leachables are not always a subset of extractables. As a result, regulators are requesting more leachables data that better reflect the actual risk to the patient. 

 The basic premise for carrying out E&L testing from both FDA and EMA remains the same whether it is for the container–closure system or manufacturing environment. However, expectations have increased over the years, but have recently accelerated for biological formulations because of the possible interactions of leachables with these formulations. 

				There are several areas in which regulatory expectations regarding E&Ls and general impurity assessments are changing. Through initiatives such as the forthcoming 

 General Chapters <232> & <233> involving elemental impurities, regulatory expectations of specificity, accuracy, and control are being implemented. Also, initiatives such as the recently "published for comment" glass delamination document of 

 <1660> and the increase in requests for routine extractables testing of incoming lots of container material demonstrate that the concept of control and prevention is being driven by regulatory agencies. 

 Regulatory bodies put the onus on drug companies to demonstrate that E&Ls do not pose a risk to the patient. As a rule, agencies like to see leachables as low as reasonably achievable. They also like to see that the drug companies have thought out their approach to E&L.  

One noticeable increase in E&L expectations comes with the expanded use of single-use components. In the past, there was little interest in E&L from process equipment because most facilities used stainless steel. Now, as more stainless steel is replaced with single-use equipment, regulatory bodies want more E&L data, including data from the same filters that were not a concern in stainless steel systems.  

				Regulatory expectations continue to increase. Drug–device combinations that historically garnered little regulatory attention in regards to E&L are now receiving more in-depth scrutiny. Over the past couple of years, several oral and dermal solution formulations have received either deficiency letters or specific information requests from FDA asking for in-depth E&L information for drug products. It is likely that this trend will soon spread to affect products that were traditionally considered to be at a lower risk of E&Ls as emphasis in this area continues.  

				How do regulatory expectations for E&L testing and toxicological assessments vary between EMA and FDA? 

				The regulatory expectations in Europe (EMA) and the US (FDA) are very similar. However, in my experience, variability between different reviewers within the same authority regarding what level of documentation they expect is higher than the difference in official standpoints concerning what documentation to submit with regard to the qualification of the pharmaceutical packaging materials between FDA and EMA. 

 The significant differences between the two regulatory authorities are in the amount of information supplied on how to conduct testing. FDA points to the Product Quality Research Institute (PQRI) recommendations, but the EMA guidance is a lot shorter and doesn't go into specifics. Generally, PQRI recommendations tend to be followed because they are more stringent than EMA. PQRI has a level of 0.15 µg/day for identifying species whereas the EMA has 1.5 µg/day. There doesn't appear to be any difference between toxicological assessments for either regulators, but a toxicologist would be able to confirm this. 

 Although it is difficult to predict how developing regulatory requirements may contrast, I have found the current expectations for E&L testing between EMA and FDA to be more similar than different. I believe the background that has allowed this to occur is that the development of industry E&L study concepts has coincided closely with the development of the International Conference on Harmonization. It is also notable that the E&L industry driving force of the PQRI has been a multinational effort both in its recommendation development, as well as its promotion of the developed concepts. 

 There are some differences between EMA and FDA. EMA is quicker to incorporate ICH documents and is more willing to put out guidance documents (e.g., the 2009 CHMP Guideline on the Limits of Genotoxic Impurities). FDA is more noncommittal, leaving it up to the drug company to demonstrate that E&Ls do not pose a risk to the patient. 

Experts share insight into extractables and leachables testing, including high-risk products, analytical testing, and regulatory requirements from FDA and EMA.

Examining the Growing Challenge of Extractables and Leachables

Patheon will acquire softgel-specialist company Banner Pharmacaps, based in North Carolina in the US, for $255 million. The acquisition will provide Patheon with several new products, technologies and facilities, and is also in line with the company’s intention to further develop its oral dosage development and manufacturing services. 

According to a press statement, Banner Pharmacaps is the second largest pharmaceutical business in the world focused on developing softgel formulations. The company has research laboratories and manufacturing facilities in the US, the Netherlands, Canada and Mexico. 

James C. Mullen, CEO of Patheon, said in the statement, “The transaction provides is with a well-balanced portfolio of proprietary products, state-of-the-art facilities with enhanced capabilities, as well as an expanded geographical presence. We believe our visibility with in the industry will be further strengthened as we pass the $1-billion revenue mark.”

Patheon is purchasing Banner Pharmacaps from VION N.V., a manufacturer of foodstuffs and ingredients based in the Netherlands. VION intends to now focus on its core business in the food industry.

The acquisition is expected to close by the end of this year. 

Patheon will acquire softgel-specialist company Banner Pharmacaps, based in North Carolina in the US, for $255 million

Patheon to Acquire Banner Pharmacaps

Dr. Reddy’s is planning to acquire the specialty injectable company OctoPlus for approximately EUR 27.4 million ($35.7 million) in cash to strengthen its technological capabilities in drug delivery. The companies have reached a conditional agreement on the acquisition and a formal offer memorandum is expected shortly. The offer of EUR 0.52 per share represents a premium of OctoPlus’ most recent closing price and was unanimously approved by the OctoPlus board.

, Dr. Reddy’s has been following the activities of OctoPlus for some time and is particularly interested in OctoPlus’ expertise in drug formulation and difficult-to-formulate injectables. Following the acquisition, Dr. Reddy’s intends to position OctoPlus as a complex injectable research center. In addition, OctoPlus’ identity and head office will be retained.

One of OctoPlus’ lead product candidates is Locteron, a controlled-release formulation of interferon alpha that is currently in clinical trials as a potential treatment for hepatitis C. OctoPlus was developing the drug with Biolex Therapeutics. However, Biolex filed for bankruptcy earlier this year.

“The intended public offer price reflects the value of OctoPlus after the recent value erosion of Locteron,” Jan Egberts, CEO of OctoPlus, explained in the press statement. “Over the last few months the value of Locteron has significantly eroded, due to the ongoing emergence of all oral hepatitis C treatments, which ultimately resulted in the recently initiated bankruptcy liquidation filing of Biolex.”

According to Egberts, OctoPlus has reviewed several strategies for the company and believes that the intended offer by Dr. Reddy’s will be the best option for the company.

Dr. Reddy’s says that it does not expect the global number of employees of the combined company to materially change because of the offer. However, OctoPlus’s supervisory board will be reduced from five to three members.

The offer memorandum is expected to be submitted for approval within five weeks and the offer, if made, will commence during the first half of December.

Dr Reddy's is planning to acquire the specialty injectable company OctoPlus for approximately EUR 27.4 million ($35.7 million) in cash to strengthen its technological capabilities in drug delivery.