Pfizer and GlaxoSmithKline have entered into separate agreements with the GAVI Alliance to supply pneumococcal vaccines to developing countries. Each company has agreed to supply as many as 480 million doses of their pneumococcal vaccines 

In a deal worth almost €2 billion, Bristol-Myers Squibb has commenced a cash tender offer to purchase all outstanding shares of Inhibitex. The transaction will provide BMS with an oral nucleotide polymerase inhibitor that is currently in Phase II development for the treatment of hepatitis C.  

Sanofi is extending a helping hand to start-up biotech company Warp Drive Bio by providing funding, access to its strains library and expertise in natural products. Two US venture capitalist firms will also invest in the start up, with all three offering funding that could amount during $125 million in the next five years. 

Pledging to strengthen procedures and policies to ensure data integrity and comply with cGMP, Ranbaxy has signed a consent decree with the FDA. The company will also make a provision of $500 million to resolve liability in connection with an investigation by the US Department of Justice. 

How can pharma make use of social media opportunities without running afoul of regulators? Pharma companies worldwide have been waiting for an answer to this question for years, but progress has been slow. In the US, however, the FDA recently released a draft guidance entitled 

Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices

 that includes recommendations on responding through online channels such as forums and chat rooms. The guidance only deals with social media in the specific context of unsolicited information requests, but it demonstrates that regulators are considering how social media affects different aspects of pharma's business activities.  

In terms of off-label information, the internet and social media have a big role to play. Firms often encounter requests for such information about their products through websites, discussion boards, chat rooms or other electronic forums. Many companies, wary of invoking the wrath of regulators, may shy away from responding, but the guidance acknowledges that it can be in the best interest of public health for companies to step in as other participants in the discussion may not have the most uptodate information about their products. In the guidance, the FDA also states that it acknowledges that firms are capable of responding to information requests in a "truthful, non-misleading, and accurate manner". Despite this, however, the FDA is concerned about the public availability of responses. 

The FDA's main concern is that firms may post detailed public responses to questions about off-label uses of their products in a way that communicates unapproved information to those who have not asked for it, such as other participants browsing the discussion.  

The FDA recommends that firms only respond to public requests that pertain specifically to their own named products. Caution should also be taken when responding to more general questions. For example, for a question such as "What drug/device can be used for Condition X", the firm should not respond if its product has not been FDA-approved or cleared for the mentioned condition. A safer question to respond to is a specific request such as "Can Drug/Device Y be used for Condition Y", where Y is a named product of the company. To alleviate the concern mentioned above, however, the FDA states that the reply should be limited to providing contact information that allows people to follow up through a one-to-one phonecall or email. 

If a firm responds to unsolicited requests for off-label information in the manner described in the draft guidance, the FDA said that it will not use such responses as evidence of a firm's intent that the product be used for unapproved or cleared uses. 

In Europe, news on social media regulations has been quiet. Last year, however, the Association of the British Pharmaceutical Industry (ABPI) published a guidance that suggested best practices for managing adverse events and other pharmacovigilance data from the internet and social media tools. Read more about this at 

Although the FDA and the EMA work differently, they tend to draw from one another's regulations and guidelines. The FDA's draft guidance could eventually impact how European regulators approach social media issues.  

The FDA is developing additional draft guidances that deal with social media, but the agency says that it is difficult to provide a timeline for their issuance because of extensive work and review processes. According to a note on the FDA website, the main priority areas the agency is striving to address are fulfilling regulatory requirements when using tools associated with space limitations, fulfilling postmarketing submission requirements, on-line communications for which manufacturers, packers, or distributors are accountable, use of links on the internet and correcting misinformation. 

If European regulators do decide to follow guidances from the FDA, however, it will take time for them to be transferred to Europe. In particular, the ban on direct-to-consumer advertising could make it more difficult for European companies to exploit social media. 

Articles

News

How can pharma make use of social media opportunities without running afoul of regulators?

News: FDA's Social Media Insight

Q: Cloud computing has become more prevalent in recent years and the introduction of Apple's iCloud service will certainly increase uptake by the masses, but how does it compare with in-house computing?

Although services such as Apple's iCloud or Amazon's Web Services will see the mass appeal of cloud computing increase, this will predominantly be on the consumer level rather than an enterprise one. However, irrespective of the vendor, when comparing cloud computing to in-house computing, the main benefit is that the whole ecosystem is managed entirely by the vendor. As a result, pharmaceutical companies can experience the business benefits of an efficient IT infrastructure without having to manage legacy programmes or software updates. In an industry that is increasingly facing budget constraints, being able to reduce hours spent on administrative tasks can be hugely beneficial as time can be better spent on activities that drive competitive advantage or business development. 

Q: Is cloud computing currently being used at all by pharmaceutical companies and, if so, is the technology being used to its full potential? 

Some forward-looking companies have already invested in cloud computing and are realising the benefits. Pfizer, for example, has trialled the use of cloud computing to conduct online clinical research with customers and is now using it to deliver real-time information to its global sales team (1) . In addition, The Pistoia Alliance, an industry body formed by informatics experts from leading pharmaceutical companies including AstraZeneca, GlaxoSmithKline and Novartis, has successfully piloted cloud-based sequence services that allow members to easily access and share their latest research. 

However, on the whole, the pharmaceutical industry has yet to harness the full potential that cloud computing has to offer. Perhaps the single biggest opportunity for the pharma sector is cloud computing's capacity to store vast amounts of data. One of the best examples of how cloud computing could benefit researchers can be found in Next-Generation Sequencing (NGS). A single NGS experiment can generate hundreds of petabytes or even zettabytes of data, which makes this research method very expensive. NGS promises to make DNA research far cheaper than is possible with the current standard dye-terminator method, but the right platform is needed to host this information. Cloud computing offers a solution by providing a vast yet scalable global processing environment. 

Companies should also be considering how cloud computing can enable the adoption of emerging capabilities, such as mobility and social media. Though the virtues of these technologies are increasingly recognised by the pharmaceutical industry, adoption often requires too many updates to existing IT infrastructures to make them viable. Cloud computing offers an environment that is quick to build and cheap to maintain. 

Q: For host companies wanting to serve pharmaceutical clients, what are the challenges in terms of security and validation in accordance with the pharma industry's stringent requirements?

The main challenge for host companies wanting to service pharmaceutical clients is one of perception. Hosts need to be able to reassure customers that data confidentiality and privacy requirements can be met satisfactorily, whether it is to do with sensitive customer information, such as clinical trial results, or information that can influence competitive advantage, such as drug discovery data.  

The current roadblock is that there are no security solutions that can guarantee 100% protection against cyber threats. Nevertheless, there are steps that hosts can take to tackle pharma's hesitancy around the security risks of cloud computing. Firstly, private cloud environments are more secure than public cloud services. As the name suggests, private clouds are only accessible to the businesses they've been created for, which means that information contained within them is not in the public domain. In addition, private clouds can be tailored to meet the regulatory requirements of each business, so companies can add their own security steps for users wanting to access the platform. Secondly, although no product is entirely secure, there are a wide range of encryption and access management tools available that cloud hosts can employ to help pharmaceutical companies feel more confident in data safety.  

Q: Security is clearly a major concern, but are there any other challenges that still need to be addressed? What is needed to encourage greater uptake of cloud computing in the pharma industry?

Security is certainly a concern for the customers we speak with, but it is not the only barrier to adoption. In fact, a concern we hear about even more frequently than security is whether cloud computing will offer sufficient return on investment (ROI). The key concern is that the ability of cloud computing to scale up and down in accordance with usage could end up putting an uncapped drain on resources. For example, pharmaceutical brands looking to adopt mobile technology for customer communications may find that usage costs are currently quite low compared with the offered rewards because adoption is not too widespread. However, companies are concerned about what will happen if the technology proves to be a success and usage increases. At the moment, there is a lack of effective financial modelling to reassure companies of the business benefits.  

One of the key factors that cloud vendors and hosts must consider is that most businesses do not care what platform their infrastructures are hosted on; rather, they are interested in the offered services. To ultimately drive cloud computing adoption, vendors need to offer more services, such as clinical trials or compliance tracking, to move conversations from basic 'horse power' to real business benefits. 

Q: How would a pharma company go about migrating certain computing services to a cloud? 

There are several key steps that pharmaceutical companies should address when looking to migrate computing services to the cloud. Firstly, the IT team must choose a service that can be used as a proof of concept. The team should look for a service that has some dimension of scalability and specific security requirements to ensure flexibility and data protection. Secondly, the IT team should choose a service that requires new capabilities or which does not have suitable existing infrastructure. NGS is a great example of this because the demand on computing power is one of the biggest challenges for pharma companies. With its flexibility and large storage capabilities, cloud computing has the potential to offer the perfect environment for NGS and can act as a great case study for the business. Thirdly, once the right service has been selected, a clear migration roadmap, with measurable goals, is vital to show the on-going ROI of a project. Lastly, throughout this process, it is important that the team effectively communicate the project's progression and business benefits to the management team to ensure that adoption is continually aligned to the company's broader goals.  

Q: Looking ahead, how do you think cloud computing will advance? How might this affect the pharma industry?

Cloud computing offers the pharmaceutical sector a chance to cut the cost of global collaboration and help drive research efficiency by enabling more effective information sharing. Cloud computing is here to stay and while we've already seen some great examples of what it has to offer, the pharmaceutical sector has to maintain this momentum. If pharma companies are to truly adopt cloud computing, they should be able to convert many of their fixed costs, such as IT infrastructure and software licensing, into variable costs to help better manage their fluctuating revenue streams. In return, the service providers themselves will have to start offering higher end services, such as business processing, which will help reduce even more substantial parts of a business' fixed costs. 

is associate vice president, life sciences, at Infosys. 

1. C. Books, "Amazon touts Pfizer and other wins in the enterprise", (SearchCloudComputing, 2010). 

http://searchcloudcomputing.techtarget.com

Ask the Expert

We interview Subhro Mallik from IT firm Infosys about how pharma is responding to the cloud computing phenomenon and what more can be done to realise business benefits.

Head in the Clouds

"The patent expiry of several major blockbuster drugs worth $150 billion [€119 billion] between 2010 and 2017 will fuel the growth of the global generic pharmaceuticals market," so says a press release announcing new analysis from Frost & Sullivan. Good news for generics companies and for patients who will potentially have access to lower cost medication, but what about Big Pharma? This lost revenue comes in the midst of an economic low and at a time when R&D pipelines are looking a little shaky. It is unclear as to whether this number also includes biosimilar opportunities; if not, then it could be double trouble. It was interesting to read in the media this week two quite different strategies to counter the patent cliff.  

In anticipation of the patent expiry of Diovan (valsartan, a medication to manage high blood pressure), Novartis recently announced a US workforce restructure totalling some 2000 job losses, mainly in sales. While Novartis acknowledged that the steps to be taken were difficult, it also stated that they were necessary to free up resources to invest in the future—presumably in the form of strengthened R&D efforts. The changes are expected to take place in the second quarter of this year.  

On the other side of the coin though, according to recent reports, Pfizer's Lipitor sales have levelled off rather than continuing to plummet since losing US patent protection on November 30. If media reports are to be believed, the reason for Pfizer being able to hang onto a lion's share of market is down to fighting hard on the frontline of sales and a heavily advertised copay programme called "Lipitor For You". This is a somewhat unusual tactic; in the past, generic competition and subsequent declining revenue was considered a lost cause. All eyes are on Pfizer. 

This optimistic versus pessimistic approach puts me in mind of questions over R&D strategies. Hopeful companies are throwing extra resources at R&D while others are cutting back, but frankly, neither camp is fully confident about the risks of their choice.  

One thing is certain: generics are destined for continued growth. The question that remains is what effect spiralling prices from increasing cost competition could have on quality. 

"The patent expiry of several major blockbuster drugs worth $150 billion between 2010 and 2017 will fuel the growth of the global generic pharmaceuticals market," so says a press release announcing new analysis from Frost & Sullivan.

Cliffhanger

However 2012 ends up, it will be a dramatic year for Servier. The French company has a number of ongoing collaborations that could lead to a new generation of products, but any positive news from these developments is likely to be overshadowed by the ongoing safety scandal of its diabetes treatment Mediator (benfluorex hydrochloride), which was withdrawn from the market in 2009. A major court case is set for mid-year and the controversy continues to implicate an ever-growing list of prominent people in France. The scandal receives regular coverage in the French media, some of which has drawn an angry response from Servier's legal team (1). It is also worrying for the pharmaceutical industry as a whole because the developments are prompting changes in the way that drugs are approved in France (2). 

Servier has always prided itself as being different to other pharmaceutical companies (3). Although it is among the top 10 companies in Europe and ranks among the top 30 worldwide, it remains an independent company. In 2004, Servier's ownership structure was changed to a foundation to prevent takeovers. According to the company's founder, Jacques Servier, this is the best way to enable continuity for the company's mission.

Its publicly available information highlights the difference between itself and other companies and this has been emphasised by its founder in his rare interviews (4, 5). For example, Servier states that it reinvests a higher proportion of its turnover back into its research. Whereas the top ten pharmaceutical companies reinvest 14% of turnover, and French industry as a whole reinvests 9%, Servier reinvests 25% (3). Servier refers to this as the "invent or die" principle, citing the fact that it has synthesised 50 000 chemical entities as evidence of its innovation credentials.

Another aspect of the company's independent approach has been its internationalisation strategy. It is now present in 140 countries and 90% of its medicines are used internationally. This success stems from adopting a global strategy early on. For example, the company established itself in eastern Europe before the fall of the Berlin wall, which meant that it was well positioned in the aftermath. In 1998, a major economic crisis hit Russia and prompted a number of US companies to withdraw from the market, but Servier chose to stay and has since benefited from the market resurgence. 

At present, the company is banking on a number of collaborations bearing fruit in the near future to continue its strong growth. In January 2012, Servier announced a deal with the Swedish company BioInvent International under which Servier will use BioInvent's technology to select an antibody candidate for the development of an unspecified oncology target (5). At the end of 2011, Servier also entered into an agreement with MacroGenics, a US biotech company, for the development and commercialisation of MGA271, a first-in-class monoclonal antibody candidate that is being studied in Phase I for the treatment of solid tumours. The deal is potentially worth $470 million (5, 6). Servier also has an ongoing alliance with Belgian biotech firm Galapagos to develop a novel osteoarthritis drug, which led to a milestone payment of €4 million from Servier in December 2011 (7).

Unfortunately for Servier, most mention of its name at present is connected with Mediator. The drug was originally on the market as a diabetes treatment, but became widely used off label for weight loss (8). In 2009, it was revealed that the drug might be linked to 500 deaths in France, and media and public outcry led to its removal from the market (2). Astonishingly, Jacques Servier was quoted in the French media as saying that there had been no more than three deaths due to Mediator, which prompted an angry reaction from the Health Minister Xavier Bertrand (9). 

The French regulator, the Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS), was criticised for not acting on earlier information that structurally similar drugs could cause valvular heart disease and pulmonary arterial hypertension (8). Regulators in other European markets and the US had taken strong action over related agents and there is still anger as to why similar action was so slow to take place in France. The Mediator scandal has also had a dramatic effect on the regulatory mechanisms of the French healthcare system. In January 2011, the head of the French regulatory agency was forced to resign and the agency has since also been renamed the National Agency for the Safety of Medicines and Health Products (ANSM) (10).  

Although acknowledging that safety regulators had missed a series of warning signs in previous years, the French government has pointed the finger at Servier. However, it has been difficult for the government to totally shift the blame after an interministerial commission revealed that voting members of the approval committee had been allowed to simultaneously serve as consultants or employees of the companies they were supposed to be regulating (11). 

Such revelations have led to an overhaul of the French system, and in December 2011, a law to reform how drugs are approved and regulated was adopted by the parliament (2). Under the new system, potential new drugs must be compared with existing approved therapies rather than just with placebos, if they are to be reimbursed under the public health insurance system. Furthermore, greater transparency is being insisted on, with pharmaceutical companies being forced to declare their links with outside organisations and individuals or face criminal sanctions for failure to comply (2). The new law is still in development, but has been criticised over certain aspects, such as an additional clause that states that a drug will be reviewed every five years regardless of problems. The French pharmaceutical industry body, les enterprises du medicament (LEEM), has also expressed concerns at clauses in the new law intended to restrict visits by sales representatives and ban company-funded medical education (12).  

Patient groups have launched a number of legal cases against Servier and in December 2011, the Cour de Cassation, France's highest criminal and civil court of appeal, rejected a request from Servier, for all lawsuits being brought against the company to be consolidated into a single trial (13). This is a major setback for Servier as the cases are likely to drag on for several years. One of the first cases will be a trial before the correctional court of Nanterre, where Jacques Servier himself and several executives of the company will face charges of "deception", which they were charged with in September 2011 (13). Beyond this, the company's executives face more serious charges for "involuntary homicide and injuries" (13).  

Public demand for someone senior to be held accountable is high and the authorities will be keen to be seen as dispensing justice. Jacques Servier risks a maximum prison sentence of four years and the company is likely to face huge claims for damages. The worst-case scenario could see the company lose its operating license. 

Servier's R&D successes this year will be pushed into the background as further details about Mediator emerge. The ongoing case also has wider ramifications because it may set a precedent for future cases involving drug safety issues. It is unusual for a company's top executives to be named and shamed, and the Servier case shows that in serious cases involving public health, senior people may find themselves on trial. Equally, regulators will be under greater scrutiny and are likely to become increasingly conservative because any oversight may come back to haunt them.  

The pharmaceutical industry as a whole will also be concerned that the fallout from the Mediator case will cloud the public's views over what can be considered acceptable regarding the risk–benefit profile of products. The industry's interactions with regulators and healthcare professionals will also come under greater scrutiny. Servier has often publicly highlighted how it differs from other pharmaceutical companies in the way it operates its business, but the irony is that critics of the pharmaceutical industry will consider Servier's actions as typical of the sector. The Mediator case has already led to changes in the way that France approaches the regulation and promotion of medicines. Whatever emerges over the next year also has the potential to influence markets in other countries, which will be keen to safeguard against any flaws proven in the French system.

1. E. Lanez, "Mediator : l'effarante boîte à mensonges" (Le Point.fr, 2011) 

2. B. Casassus, "With New Law, France Revamps Drug Approval" (

3. Servier, "Research is as vital as being an industry " (Servier website, 2011). 

4. J. Upton, "Servier: patience and passion," 

5. Focus Reports, "Interview—Jacques Servier" (2011). 

6. K. Grogan, "Servier signs cancer deal with Sweden's BioInvent" (

7. European Biotechnology Science & Industry News "Galapagos gets €4 million in alliance with Servier" (2011). 

9. Le Point.fr, "Mediator, un jugement pour 2012?" (2011). 

10. S. Sayare, "Scandal Over Mediator, a French Weight-Loss Drug, Prompts Calls for Wide Changes" (

www.assemblee-nationale.fr/13/rap-info/i3552.asp

12. InPharm, "2011 Year In Review" (2012). 

, "Mediator: la cour rejette le regroupement des procédures" (2011). 

Industry Insider

The scandal surrounding Servier's diabetes drug, Mediator, continues to unravel in France and could have implications for the whole pharmaceutical industry as the country scrutinises its regulatory systems.

2012: A Good, Bad or Ugly Year for Servier?

Gamma rays are a form of electromagnetic radiation—like x-rays, but with higher energy. The primary industrial sources of gamma rays are radionuclide elements such as Cobalt 60, which emit gamma rays during radioactive decay. Gamma rays pass readily through plastics and kill bacteria by breaking the covalent bonds of bacterial DNA. They are measured in units called kiloGreys (kGy) 

Gamma irradiation provides a number of benefits in cost and sterility assurance. It can be applied under safe, well-defined and controlled operating parameters, and is not a heat- or moisturegenerating process. Consequently, there is no heat stress and condensate drainage or outgassing are not required. Most importantly, there is no residual radioactivity after irradiation. 

Beyond having a different lethality mode, characterising the radiation sensitivity of the product bioburden is another key difference from moist heat (steam) sterilisation. Radiationresistant biological indicators are not used. After the mean bioburden is quantified and sensitivity to a low radiation dose (~8-10 kGy) is established, a statistically determined higher dose (typically >25 kGy) can be applied to provide the appropriate sterility assurance safety margin for every unit in the batch. This safety margin is similar to that of moist heat sterilisation, where a target of <10–6 probability of a non-sterile unit (Sterility Assurance Level, SAL) is established. 

A third difference is that the gamma dosage can be measured in each batch using detectors called dosimeters, which enable parametric release. Product batches subjected to gamma radiation do not need to be lotsample sterility tested for release. 

Standards for validation of gamma sterilisation

Validation procedures for the sterilisation of single-use systems via gamma irradiation are well established and based on widely used industry standards. These standards are recognised by regulatory agencies globally in lieu of any specific regulatory guidance.  

The international standards are harmonised among three official standards bodies: the American National Standards Institute (ANSI), the American Association of Medical Instrumentation (AAMI) and the International Standards Organization (ISO). Their common document is ANSI/AAMI/ISO 11137, Sterilization of Health Care Products — Radiation (1).

ANSI/AAMI/ISO 11137 comprises three parts: Part 1 covers requirements for development, validation and routine control of a sterilization process, Part 2 covers establishing the sterilization dose, and Part 3 provides guidance on dosimetric aspects, the measurement of the radiation dose. Part 2 describes 3 methods for establishing a sterilizing dose (with SAL <10-6). Methods 1 and 2 were designed with small medical devices in mind and involve determination of bioburden and multiple dose analyses that require over 100 or 200 units respectively, both for initial validation and for quarterly dose lethality audits. When we consider large single-use systems, which are made in relatively small batches, both of these methods can be very costly and time consuming. However, the standard provides a third method called VDmax (VD stands for verification dose). Rather than determining the minimum dose to achieve a SAL of <10–6, the VDmax Method substantiates the suitability of a predetermined dosage level, specifically 25 kGy or, for plastic devices with lower gamma tolerance, 15 kGy. 

In conjunction with the publication of the VDmax method for doses of 25 or 15 kGy, additional doses were qualified and published by AAMI in their Technical Information Report 33:2005 (2). This is considered a supplement to ANSI/AAMI/ISO 11137 and they will likely be merged at the next scheduled revision. It expands the VDmax method to seven additional dosages; 17.5, 20, 22.5, 27.5, 30, 32.5 or 35 kGy, enabling flexibility of minimum sterilising dosage based on mean bioburden levels for the product. 

The VDmax method still requires at least 40 systems; 30 for bioburden testing (10 from each of three lots) and 10 units for sterility confirmation after low dose exposure. That's a lot of systems and a primary reason to consider simply irradiating at >25 kGy and claiming microbial control wherever a validated sterile claim is not required. 

Once the mean bioburden and minimum validated sterilising dose is established, and the product goes into production with a sterile claim, quarterly dose audits are conducted to confirm that the levels of bioburden and/or their sensitivity to gamma irradiation have not changed over time. These quarterly dose audits require an additional 20 units from a current lot each time; 10 for mean bioburden analysis and 10 for irradiation at the low verification dose and sterility testing. If any of the irradiated units are found to be nonsterile, the test must be repeated at a higher verification dose, which will then qualify a new, higher production sterilisation dose for subsequent batches to return the process to a <10–6 SAL. 

Addressing technical difficulties with testing of single-use systems

Because of their size and complexity, single-use systems can present some technical difficulties when assessing bioburden and sterility after irradiation. Fortunately, the standard provides some practical strategies by allowing for the grouping of similar products into families so that validation only needs to be performed with a "worst case" or representative unit. Product families are defined by common nature and source of raw materials, components and product design and size, along with assembly process, equipment and environment, etc. A single Master Product can then be identified or constructed to be the representative or "worstcase" version of all the products in the family. Sterilisation of comparable products in the family can then be rationalized as equivalent to the validated Master Product. 

While this reduces the number of different systems that need to be qualified, bioburden recovery and sterility testing of large complex systems can still present formidable technical challenges. Therefore, it is common to only validate sterility of the internal product fluid contact pathway (with closures at any ports or openings) The system exterior and inner packaged space, which receives the same radiation dose, can be considered microbially controlled, but not validated as sterile.  

To further ease the technical challenge of aseptic handling for bioburden and sterility testing, the Master Product can also be broken into smaller subunits, termed Sample Item Portions (SIP). These can be tested separately and have their mean bioburden and sterility results combined to establish the validated sterilising dose for the fully configured system.

Radiation steriliser — dose mapping and quarterly audit

Cobalt 60 can be stored safely in a pool of water, while the chamber above the pool is surrounded by a thick concrete barrier that prevents gamma rays from escaping when the gamma source is elevated into the irradiation chamber. Product intended for sterilisation is packaged, palletised and transported into the irradiation chamber using a conveyor. 

Once a minimum sterilising dose is established for the Master Product, a pallet load configuration and density is established. Dose measuring devices called dosimeters are distributed throughout the packaged load to confirm that the minimum sterilising dose is reached throughout the batch. Because the received dose can vary based on density, materials are typically qualified to withstand up to 50 kGy. On a quarterly basis, the process is audited by, again, determining bioburden in 10 current product, Master Product or SIP samples. Verification dose sterility tests are conducted on 10 additional samples.  

The sterilisation validation and irradiator batch data support both the supplier's claim for sterility for the singleuse system(s) and the user's claim for cellculture process control and finished product sterility. Several documents serve to support both system and finished product sterile claims. First, the supplier should provide a letter explaining the rationale for the sterile claim of each specified system by part number, based on actual or Master Product validation. Suppliers can insert a Certificate of Quality within the unit packaging stating that the product is sterile after irradiation. External irradiation indicators that change colour upon exposure are not sufficiently quantitative to confirm sterility. A summary Sterilisation Validation Report supporting the minimum sterilising dose, as well as the Dose Mapping Study Report and most current Quarterly Dose Audit Report generated by the irradiator, should be provided by the system supplier. Original data and irradiator certificates, however, may only be available during supplier audit. Lastly, the supplier should provide a Certificate of Irradiation for the system lots in the batch, certifying the minimum dose recorded by the batch dosimeters. 

This combination of sterilisation validation rationale, minimum dose sterilisation validation, batch load dose map, batch irradiation dose certificate and quarterly dose audit serves to support the ongoing sterility of the single use system and the sterile products produced with them. For more information on this subject, a good resource is available free of charge in the form of the BPSA's Guide to Gamma Irradiation and Sterilization (3). 

1. AAMI/ANSI/ISO 11137:2006, "Sterilization of health care products — Radiation — Part 1: Requirements for the development, validation and routine control of a sterilization process for medical products; Part 2: Establishing the sterilization dose; Part 3: Guidance on dosimetric aspects"(2006).  

2. American Association of Medical Instrumentation, "Sterilization of health care products—Radiation—Substantiation of a sterilization dose—Method VDmax", Technical Information Report TIR33:2005 (2005). 

3. BPSA, "Guide to Irradiation and Sterilization of Single-use Systems" (2008). 

Disposables Advisor

This column will address some of the questions on how single use systems are sterilized by gamma irradiation and what documentation may be requested by regulators.

Understanding Gamma Sterilisation

By Kashyap R. Wadekar, Mitali Bhalme, S. Srinivasa Rao, K. Vigneshwar Reddy, L. Sampath Kumar and E. Balasubrahmanyam

To ensure the quality of APIs and finished drug products, impurities must be monitored carefully during process development, optimization, and process changeover. The isolation, characterization, and control of impurities in pharmaceutical substances are being reviewed with greater attention based on national regulatory and international guidelines. In Part I of this article, the authors examine the different types and sources of impurities with specific examples. 

This article was also published in our US sister publication 

Peer-Reviewed Research

In Part I of a three-part article, the authors discuss what constitutes an impurity and the potential sources of impurities in APIs and finished drug products.

Evaluating Impurities in Drugs (Part I of III)

Q: Nanotechnology is often hyped as either a miracle cure-all or a potential danger. How much of this is grounded in truth and what is the practical reality of the technology?

The rational design of advanced drug delivery systems and innovative nano-sized therapeutics (nanomedicines) began almost half a century ago. There are already more than 40 products approved by regulatory agencies for routine use, and many more technologies are also in clinical development. These first-generation products are making an important contribution and are seen to be safe and efficacious with an adequate risk–benefit. Follow-on products are also starting to emerge, as well as novel second-generation nanotechnologies that can be used as therapeutics, imaging agents and combined theranostics. 

Innovative nanoscience in concert with the increased knowledge arising from genomics and proteomics research is creating exciting opportunities for nanomedicine development using advances in materials science and, in some cases, innovative therapeutics such as siRNA and aptamers. There is also real potential to develop novel multicomponent systems (e.g., those involving gold or iron nanoparticles, and polymers and therapeutics as single agents or combination therapies). More in depth discussion about the opportunities and challenges in these areas can be read in a Duncan and Gaspar paper (1).  

Q: What new therapies can nanotechnology enable?

To answer this question, I advise readers to take a look at an interesting historical overview by B. Munos (2). He explains that during the last 60 years, the FDA has approved approximately 1200 new chemical entities, as well as around 120 biologicals/proteins. Roughly 40 nanomedicine products have also reached the market, which is interesting given the relatively minor investment of pharma companies in this area compared with that for low-molecular weight chemical entities and biotech products. 

In the coming years, I believe we will see an increasing number of nanomedicine products. Consider for instance that low-molecular weight synthetic chemotherapy was only born at the beginning of the last century. 

In my view, some of the particularly interesting opportunities/advances in nanomedicines include:  

A combination therapy with liposomes containing two drugs is already in Phase I/II development by Celator Pharmaceuticals (US). 

Polymer therapeutics—several polymeric drugs, polymer-proteins/polymer aptamer and block copolymer micelles are now on the market and there is a strong pipeline for further clinical development

New manufacturing techniques and template manufacturing (PRINT approach) that are applicable to many areas of advanced drug delivery. Interesting insight can be read in a Petros and  DeSimone paper (3).

New opportunities for intracellular/cytosolic delivery of macromolecular therapeutics.

Continuing efforts to improve the delivery of poorly soluble or unstable drugs, improve disease specific targeting and create new technologies for vaccine delivery. 

Q: How fast (or slow) has the pharma industry been to embrace nanotechnology? 

The 40 or so first-generation nanomedicines on the market began to arrive in 1990 and now there are many follow-up products and novel nanotechnology approaches in pipelines. In particular, specific technologies, such as nanocrystals, have been rapidly embraced over the last decade because they can help solve specific formulation challenges, such as poor water solubility.  

When all these technologies emerged as first in class, they were, as with any new, high-risk technology, embraced very slowly by pharma companies. However, once a technology has arrived in the market, there is always a sudden burst of interest, particularly as some products gain blockbuster status. With nanotechnology now well established, coupled with the high-drug attrition rate for low-molecular weight chemical entities, interest in this area has certainly increased.  

Q: It has been claimed that many Big Pharma companies are losing interest in nano-enabled drugs. Do you agree with this statement? 

This statement is not true given my understanding of the term "nanomedicine". It is always dangerous to make generalisations such as overhyping a field at the outset and then over condemning it later on. 

Certainly, parenteral drug-targeting strategies have never been an easy fix and scientific experts in this area have always known that. There are too many claims of 'platform technologies' that able to deliver any drug candidate, but this is naive because every system needs to be optimised on a case-by-case basis. 

Many basic science publications claim that new technologies—not only nanotechnology—are not practical for translation/industrial development. This can be because of:  

difficulty in achieving reproducible quality 

safety issues regarding the dose and route of administration 

issues regarding scale-up potential or cost/practicality for clinical use. 

However, if you look at the drug attrition rate for candidates that have entered clinical trials, I don't believe that nano-enabled systems have fared any worse than traditional low-molecular chemical entities. I think more data in this area would be beneficial.  

Q: How are regulators addressing nanotechnology?

The development and routine use of nanomedicines is not new. Regulators review each new technology on its own merit and make an integrated assessment of quality, safety and efficacy to understand whether the risk–benefit profile is acceptable. This will continue to happen for all medicines, nano or otherwise.  

With the advent of novel nanomaterials and the growing interest in complex, multicomponent nanomedicines, regulatory agencies continue to review all specific/emerging needs in this field. Both the FDA and the EMA have established specific teams to address nanomedicines at both national and international levels. 

Q: What key factors are necessary to develop practical, safe and effective nanomedicines?

As with any medicine, an understanding of the critical product attributes that govern safety and efficacy is vitally important, as well as the ability to ensure characterisation of these parameters using validated analytical techniques. With nanomedicines, it is also important to consider the route of administration, dose, frequency of administration, fate of the nanomaterial (all components from the product), any detrimental bioactivity, antigenicity, immunogenicity and haematocompatibility. 

As nano-sized medicines often display very different pharmacokinetics and body distribution compared with low-molecular chemical entities at the whole body and cellular level, the pharmacokinetics–pharmacodynamics relationship needs to be carefully considered during the establishment of critical product attributes relating to safety and efficacy. For each product, it is also essential to consider the proposed clinical setting for use. 

is Professor Emerita at Cardiff University (UK), and visiting professor at CIPF (Spain) and the University of Greenwich (UK). 

 R. Duncan and R. Gaspar, "Nanomedicine(s) under the microscope", Mol. Pharmaceutics online, DOI: 10.1021/mp200394t, 5 Oct., 2011. 

 B. Munos, Nat. Rev. Drug Discov., 8(12), 959–968 (2009).  

 R.A. Petros and J.M. DeSimone, Rev. Drug Discov., 9(8), 615–627 (2010). 

Interview

Does nanotechnology offer a cure-all or a kill all? We speak with Ruth Duncan about the real potential of nanomedicines.

Decoding the Hype and Fear of Nanomedicines

Q: Why has patient self-administration of therapies become such an important driver in the healthcare and pharma sectors? 

Self-administration therapies have become an important driver in the healthcare and pharma sectors for a number of reasons. Empowering patients and giving them the freedom to take medications at home or while on the road is more than just a trend; it is vital to the economic viability of healthcare systems worldwide. Enabling patients to self-administer their medication means that healthcare practitioners can use their time more effectively. Most importantly, it has the potential to save money as fewer trips to the hospital can amount to millions in healthcare cost savings. 

This trend has had a significant impact on the evolution of injectable drug delivery technologies. Many people are familiar with self-administered medications, such as inhalers for treating asthma, but few individuals, other than diabetics, have experience of injecting themselves using a syringe. As a result, drug delivery companies have had to develop devices that are both intuitive and safe. With the increasing number of approvals for new biologics in recent years, demand will also be quite strong for auto injectors and pen injectors. However, developing and producing an injection device that is safe, ergonomic, easy to use and accurate enough for a patient to self-administer involves meticulous designs, innovative technologies and consistent manufacturing. For example, the spring mechanism inside an auto injector controls the force and timing of the injection and is designed to accommodate the desired injection specifications, while the outer shell of the device may be affected in size and design by the primary container inside and human factor constraints. Once a proven mechanism is designed, ensuring consistent manufacturing then becomes vital because quality needs to be built into every device produced. At this time, there are only a few companies in the world that can design, develop, manufacture and assemble these pen-like devices, and these companies will need to work closely with biopharmaceutical partners to ensure that patients get the best drug delivery devices possible for their given therapeutic area. 

There is a growing prevalence of individuals living with chronic disease in the world. However, the good news is that pharmaceutical medicine is working in order to keep pace with this increase. Advancements in therapeutic agents and medicine have resulted in the availability of more sophisticated biologics for the treatment of many chronic diseases. In addition, there is a growing trend in self-administration medicines where patients can self-medicate. This trend has supported the need for further advancement in self-injection technology. 

These biologics often have complex technical requirements for injection. For example, they have higher volume or are more viscous, so the technical specifications of these biologics is more challenging and requires complex delivery technology. This growing trend explains why self-administration has become so important. In this respective, device manufacturers must be proficient in patient-centric design and should consider the ergonomic and human factors.  

Integrating those biologics with the right delivery system has become critical, not only from a technical specification standpoint, but also from a competitive perspective. The competitive dynamics for new drugs in different fields will require different considerations in the selection of an injection device. Patient consideration is also a factor; for example, a patient with rheumatoid arthritis may have dexterity issues, requiring certain design specifications to make the device intuitive and easy-to-use. In this respective, it's important for device manufacturers to be proficient in patient-centric design and to consider the ergonomic and human factors.  

Integrating the primary container with the secondary device successfully is also critical. Companies offering self-administration technology need to have that expertise in order to improve performance of a drug device solution, reduce risk of failure and accelerate speed to market for customers. 

Rising healthcare costs mean that treating patients is becoming more and more expensive. If a patient can self-administer their medication then this reduces the time they need to spend with a healthcare professional and, thus, reduces cost. Most medications can be taken orally, but many peptides and proteins have to be injected to ensure they are not damaged by the acidic environment in the gastrointestinal tract. If a patient is to be trained to self-inject, however, then the technology needs to be simple to ensure that it is operated correctly. In addition, medication compliance is a serious issue with many patients; the easier and more convenient the product is to use, then the more likely the patient is to take their medication. These needs for lower cost of goods, ease of use and convenience are also shaping the evolution in drug delivery technologies suitable for self-injection. 

 Self-administered products currently account for about half of the of therapeutic biologics market. The simple reason for this is that more biological agents requiring injection are being used in chronic conditions, such as rheumatoid arthritis, psoriasis and multiple sclerosis. Since it is both costly and inconvenient for patients to go to their healthcare provider to administer these biologics daily or weekly on a chronic basis, the burden falls upon the patient. Fortunately, technologies exist that make the self-medication process as comfortable and easy as taking a pill.  

Q: Which technologies (autoinjector, prefilled syringes etc.) are most suited for self-administration and why?

As patients are not medically trained, empowering them to feel comfortable enough to properly inject themselves requires a device that can make them feel safe both mentally and physically. To address this, devices with special features and technologies, such as the auto injector, are often designed so the patient never sees the needle and may finish administering the drug within a relatively short period of time. While reactions to physical pain may vary for each patient, the mental pain connected to visually seeing a needle inject can largely be reduced, especially when the patient also has control over when to initiate the injection. As a result, auto injectors are becoming a commonly accepted drug delivery technology for self-administrated injectable therapies. 

However, it is very important to note that each patient needs to be properly trained on how to use such devices and they must be provided with very clear instructions for use. The use of picture-oriented instructions and video has been a good step towards addressing this issue. Another potential drawback related to self-administration technology is the cost associated with developing a drug delivery device and the actual cost of each device. At this time, it is much easier for larger biopharmaceutical companies, which have the necessary financial resources, to initiate these programmes. Additionally, the market value of the drug must be able to justify the cost of the device. 

The most suitable technology depends on many factors:  

Technical specifications. A high volume or highly viscous biologic, which may be infused in a hospital setting, may require a patch injector/patch pump to deliver the medicine in the home setting. It is also important that careful consideration is given to the delivery of drugs that have a unique viscosity or volume that needs to be delivered.

Competitive dynamics. Pharma and biotech companies are increasingly looking to their device as a source of differentiation.

Patient factors. Certain patients will have certain needs and preferences given their condition and how mature that market is with devices. 

Frequency of administration. Whether a drug is injected on a daily basis, versus a weekly or monthly basis, is also an important factor (along with the cost factor).

All these considerations are crucial factors in selecting the right technology. For device manufacturers, it's important to have expertise across a range of delivery platforms and technologies in order to meet the above needs for customers. 

Auto-injectors and pen-injectors have been designed for self-administration. These technologies are widely used, work very well and are far easier to use and more convenient for patients than a standard needle and syringe. However, they still use a needle, which brings about issues related to needle reuse, needle disposal and needle phobia. In addition, many drugs that have to be injected are not very stable in a liquid formulation. Some biologics are stored in a powdered form to provide better stability, but they need reconstituted prior to injection, which adds to costs and treatment complexity. Liquid jet injectors avoid the issues with needles, but still incorporate a liquid formulation. They are also very expensive and have not achieved significant market traction. 

None of the technologies mentioned really provide a simple way to inject a controlledrelease formulation. Typically, a controlledrelease formulation comprises polymer microspheres in a solution, but because of the issues of needle clogging these expensive products are normally injected by specially trained healthcare professionals. Other injection technologies, such as solid dose injectors and microneedle patches, are in development, but they are not yet ready for routine patient use. 

 The key to considering self-administration technologies is to focus on the patient. Our company, for example, is not committed to any particular injection technology type. Companies should design the technical solution that best fits the circumstances in a given therapeutic application. In particular, it's important to consider the patient's needs and limitations in the target disease condition, and then to look at how best to apply technology to make the patients' self-injection experience most acceptable and successful.  

Q: What extra steps do companies need to take to have a drug approved for use in a self-administrative form?

 Generally, a biological drug will need to be first approved as an independent drug, regardless of whether or not it is to be used in a self-administrative form. For the device constituent of a combination product, the medical device manufacturer will generally support biopharmaceutical companies by filing a master access file and/or 510K to help with the customer's submission process. 

Self-administered biological drugs can generally be placed inside a primary container such as a pre-filled syringe or cartridge, which will then reside in a device that possesses the mechanical system to perform the injection. The two together is a drug/device combination product that, although not yet official, has been identified by the FDA as an area that requires regulatory guidance. Companies that wish to introduce a drug in a self-administrative form will need to start regulatory planning at a very early stage to ensure that approval times do not become a potential bottleneck to a successful global launch. 

The complexity of clinical development and the regulatory process is increasing, and companies must take every appropriate step to ensure that their products are in full compliance. In addition, companies have to bear in mind the lead times for regulatory processes. 

Any pharmaceutical product in development must undergo clinical trials. In addition, a product that is to be self-administered needs to undergo trials with volunteers and patients to ensure that the delivery system can be safely used by different patient groups in a non-clinical setting. Some of these trials may be userhandling trials, with no drug involved, just to demonstrate that the volunteer can safely use the delivery system. These trials are far simpler and cheaper to conduct than active drug trials. Once trials have been carried out for a first product, then further trials to investigate the handling and use of the delivery technology may only be required if the product is for a different patient group (e.g., elderly patients or patients with rheumatoid arthritis who may struggle to handle a delivery device). 

Q: How are designers and manufacturers of selfadministration devices approaching the challenges of ensuring sterility and accurate dosing outside of healthcare settings? 

 Accurate dosing is achieved through specially designed delivery mechanisms, rigorous testing and precise manufacturing. For example, in a mechanical device, highly accurate dosing can be achieved using the appropriate spring technologies. Thus, the design and testing of such devices is paramount. Sterility is ensured again by designing a suitable device for the primary container selected by the biopharmaceutical partner; for example, a pre-filled syringe that is assembled into an auto injector under controlled procedures in line with related regulations and standards.  

 First, it is important to consider the fact that the product will be used without the direct supervision of healthcare professionals. Companies should conduct extensive background research and ethnographic studies to fully understand the patient and the likely environment of use. The design can be established based on the findings of the investigations and the pilot device can be tested with the patient in a variety of expected actual-use settings to confirm that the product will perform as intended. 

Q: The ability to offer adjustable doses, for example in diabetes, has great potential. What progress is being made in this area?

We see progress in the development of unique and robust mechanical designs that can accommodate the need to offer adjustable doses. This allows for the device to remain cost effective, as some drugs do not have a market price that justifies complex drug delivery technology. However, we do see a renewed drive to incorporate electronics into some of the more expensive devices, which is perhaps inspired by the trend of cutting-edge designs related to smart phone and tablet innovations. 

 Technologies that provide dose adjustability have already been developed and commercialised. Cartridge-based, multidose pens, for example, have achieved excellent acceptance in the administration of insulin. Companies are now working on improving dose adjustability and confirmation of correct dose by applying advanced electronics that aids ease of use and adds intelligent features. 

Q: What are the challenges of manufacturing devices suitable for selfadministration? 

 Main challenges include anticipating numerous device usage scenarios against which to test the device, ensuring quality consistency and providing robust production lines to respond to mass production needs. To address these challenges, device manufacturers should work closely with biopharmaceutical companies to better understand end-user feedback and use it to more accurately reflect and construct usage scenarios for device testing. In addition, device manufacturers need to continually invest in the latest in-house capabilities and processes. 

 In most cases, customers will want some level of customisation; they rarely want off-the-shelf devices. The challenge for manufacturers is delivering these differentiated customised devices at an affordable cost – for both the customer and the manufacturer. Companies are utilising modular platform technology to develop and customise devices. 

The market place is also uncertain and highly dynamic. Manufacturers are B2B businesses selling devices to pharma and biotech companies. If their business changes, suffers, or is impacted, so is that of the device manufacturer. This requires methodical portfolio management and operational planning to optimise the business. 

When customers choose a device partner, they make device-based decisions, but also company-based decisions. They will be looking for factors such as a global reach and full service support, including support with global registration, and the ability to offer a differentiated benefit. 

 The most important aspect of making devices for self-administration is ensuring that they perform as intended in the hands of the patient. That means we need to first understand the patient. There are well-established ethnographic research methodologies that can be used to learn about patients and the environment in which they will use medicine. However, even today, many companies delay addressing this aspect in clinical programmes. As a consequence, products have been launched in a configuration that is clearly not well suited for self-administration. Only later, after the product fails to meet market expectations, does the company initiate programmes to address the needs of self-administration. It can be argued that keeping the configuration as simple as possible (e.g., in a vial) reduces development risk and cost, but this must be balanced against the resulting market risk, particularly when competitors introduce a product that better addresses self-administration challenges. 

Q: Needle-free devices seem to have lost some traction in the market, why might this be the case? 

 At this time, innovations in drug delivery devices with needles continue to move forward in addressing the growing need to administer biologics. Auto injectors and pen injectors have been proven to be effective, safe and reliable devices. With this established track record, needle-based devices will continue to strengthen their position in the self-administration market.  

There are two factors that may have contributed to this. Firstly, needle-free technology can be more complex, and there are various safety and operational challenges. Secondly, needles are now available that are very fine, as well as being shorter and less painful than previous generations of needles. Self-injection devices also continue to become more advanced. 

 The needle-free devices that have been commercialised are all liquid jet injectors. These devices work by firing a tiny jet of liquid through the skin. The concept was first patented many decades ago and niche products have been on the market for years. The products are either disposable devices or reusable actuators with a singleuse drug component.  

The reusable devices have been used in the past in the developing world and in the military for vaccine studies, but lost favour when the potential for cross-contamination between patients was identified. Single–use jet injectors are expensive and have never been widely used. I believe this is because the benefit of needle-free technology does not outweigh the increase in costs over alternative technologies. Liquid jet injectors will continue to be used for a number of niche products, but they will struggle to dramatically increase their market share. However, other technologies in development, some of which are needle-free, are likely to get good market traction as they are commercialised. 

It's not a matter of needle-free having lost traction; it's a matter of the matching the technology to the needs of the patient population. I have no doubt that we will see greater applications of needle-free technology as additional biologic drugs are developed for populations best served by that approach, such as paediatric patients.  

Q: What recent groundbreaking innovations have you seen in the area of selfadministration devices?

 Groundbreaking is a powerful statement. I have seen a number of significant innovations in the area of auto injectors over the past seven years, particularly when it comes to the look and the size of devices. Auto injectors are more discreet and are now available in sizes that are not much bigger than a marker pen, which allows patients to travel and use the devices whenever and wherever they wish without feeling embarrassed. Industrial designers have also worked closely with human factors engineering groups to make several devices (launching soon) that are completely customized to suit the needs of a specific patient group. For example, if rheumatoid arthritis patients have difficulty removing a cap, industrial designers can overcome this by engineering a new solution for cap removal. These may not be groundbreaking, but to me they represent a significant shift in the way devices are being made—working more with patients at the earliest stages and making drug delivery devices that are simple and intuitive. 

 The innovations I am very impressed with are the patch injectors/patch pumps. This new technology is allowing companies to deliver therapies, which historically have been infused in a hospital setting, in the privacy and convenience of the patient's home. For example, technology is in development that can allow patients to have continuous infusion at home with a ready-to-use hands-free, device. 

Special Feature

We bring industry experts together to discuss the importance of self-administration and what injection technologies are best suited to this cause.

Pharmaceutical Technology Europe-02-01-2012