Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

 on Dec. 20, 2012, a voluntary recall of three lots of the painkiller tablets, hydrocodone bitartrate and acetaminophen, USP 10 mg/500 mg, due to the potential risk that these lots (lots 3037841, 3040859 and 3042573) may exceed the potency stated on the label. The hydrocodone bitartrate and acetaminophen tablets were manufactured by Qualitest Pharmaceuticals, a subsidiary of Endo Health Solutions. Mylan repackaged and distributed the product under the UDL Laboratories Inc. label. 

 On Dec. 6, 2012, Qualitest voluntarily recalled 101 lots of hydrocodone bitartrate and acetaminophen tablets, stating in its

, that a small number of tablets from the affected lots may exceed the weight requirement and could exceed the label claim potency requirements for the ingredients hydrocodone bitartrate and acetaminophen. The affected lots, were distributed between Feb. 20 and Nov. 19, 2012, to wholesale distributors and retail pharmacies in the United States. 

 Hydrocodone bitartrate and acetaminophen are indicated for the treatment of moderate to moderately severe pain. The increased content of hydrocodone could result in more severe or frequent side effects, such as sedation or respiratory depression, especially in elderly patients who have severe kidney or liver impairment, or patients taking interacting medications, e.g., other sedating medication or certain antidepressants. Unintentional administration of a higher dosage of acetaminophen could cause liver damage, particularly in patients on other acetaminophen-containing medications, patients with liver dysfunction, and people who consume more than three alcoholic beverages a day. 

 The FDA is aware of this recall and additional information can be found on its 

Articles

Mylan issued a voluntary recall of three lots of the painkiller tablets hydrocodone bitartrate and acetaminophen.

Mylan Recalls Painkiller Pills due to Risk of Higher Dosage

 that it has extended its offer period to acquire all of the issued and outstanding shares of Pronova BioPharma, a producer of omega-3 fatty-acids. The new deadline of Jan. 18, 2013 is the maximum extension of the offer period. BASF’s cash offer stays at NOK 12.50 ($2.24) per share and remains subject to the terms and conditions stated in the 

 published on Dec. 5, 2012, including inter alia that BASF has received acceptances for more than 90% of Pronova’s total share capital. 

As of Dec. 19, 2012, BASF received acceptances under the voluntary offer for a number of shares representing approximately 67.2% of the issued shares and votes in Pronova. This figure includes a total of approximately 59.4% in Pronova’s share capital that has been pre-accepted by majority shareholders and members of Pronova’s board and management team. 

BASF’s offer received unanimous support from Pronova’s board of directors, who have recommended its acceptance. The offer is expected to close in the first quarter of 2013, subject to fulfillment of all relevant offer conditions. 

Michael Heinz, a member of the board of executive directors of BASF SE said in a 

, "We thank all Pronova shareholders that have been and will be supportive of our offer. With the chances but also the risks for the business of Pronova in mind, we firmly believe that our offer does provide full and fair value for all shareholders. We will maintain our disciplined financial approach to acquisitions.” 

To date, total acceptances received exceed two thirds of the share capital and votes in Pronova and the Oslo Stock Exchange has been notified according to the Norwegian Securities Trading Act, Section 4-2 subsection (2).

Pronova's first commercialized product, Omacor/Lovaza, is an omega 3-derived prescription drug, which is approved in the European Union and the United States. Pronova's headquarters are in Lysaker, Norway,and its manufacturing facilities are in Sandefjord, Norway, and Kalundborg, Denmark.

BASF extended its offer period to acquire Pronova BioPharma, a producer of omega-3 fatty acids.

BASF Extends Offer Period to Acquire Pronova BioPharma

Roche's MycoTOOL, which offers rapid detection of mycoplasms based on a polymerase chain reaction (PCR) test, has received FDA acceptance. This is the first commercially-available 

 PCR test accepted by the FDA for the release testing of a biopharmaceutical product that can replace traditional and time-consuming 

 detection assays which use growth on culture media and 

 assays to detect contaminating organisms.

 contamination is a common and significant issue in biopharmaceutical production, cell therapy, tissue engineering, and vaccine manufacturing. The conventional culture-based detection methods required by pharmacopoeias and drug-regulating agencies are time-consuming as they can take as much as 28 days to complete, making them laborious and difficult to interpret. Ruedi Stoffel, head of custom biotech at Roche, said in a 

, "Fast methods, like our new MycoTOOL test, will greatly enhance the efficiency, quality and safety in the manufacturing process of pharmaceutical and biological products."

 detection kit provides all critical reagents for performing sample preparation and PCR. The tool is compatible with a range of sample types, including cellular matrices (human cells, primary and continuous), canine cells, nonhuman primate cells, various rodent cell types, and cell-free matrices (culture supernatants of CHO or human-stem cells, and egg-derived samples). It also detects the broad panel of Mollicute species. The test minimizes the risk of false negative and false positive test results. The risk of undetected intracellular 

 is eliminated by lysis controls of the matrix while positive controls verify potential PCR inhibition. Nucleic acid free reagents prevent false positives, and the use of uracil-DNA glycosylase minimizes the risk of PCR carryover contamination.

Roche's MycoTOOL, which offers rapid detection of mycoplasms based on a polymerase chain reaction (PCR) test, has received FDA acceptance.

First Commercially-Available Mycoplasma Detection Test Accepted by FDA

Roche and the Innovative Medicines Initiative (IMI) have recently launched an academic-industry partnership, known as STEMBANCC, under which 10 pharmaceutical companies and 23 academic institutions will collaborate on using stem cell technology to accelerate the development of safer and more effective drugs for patients. This project will investigate the use of human-induced pluripotent stem cells for identifying drug targets and biomarkers, screening potential drug treatments, and toxicology testing. The focus will be on peripheral nervous system disorders, particularly pain; central nervous system disorders; neurodysfunctional diseases such as migraine, autism, schizophrenia and bipolar disorder; as well as diabetes. 

“The aim of StemBANCC is to generate and characterise 1500 high quality human induced pluripotent stem cell lines derived from 500 patients that can be used by researchers to study a range of diseases, including diabetes and dementia. The cell lines will help implement patient models that will facilitate the drug development process thanks to the possibility of reproducing the disease mechanism in vitro.” Martin Graf, Head of the Stem Cell Platform and coordinator of the project at Roche said in a 

The creation of the first induced pluripotent stem cells was a major scientific breakthrough that won scientists John Gurdon (Cambridge University) and Shinya Yamanaka (Kyoto University) the 2012 Nobel prize in physiology or medicine. While it is known that most adult cells can only divide to produce cells of the same type, scientists have discovered how to reprogram ordinary adult cells to create stem cells that are capable of generating various types of human cells, from cardiomyocytes to endothelial cells and neurons. These cell lines are extremely useful in early-stage, drug-development studies because they are derived from real patients and therefore contain the genes implicated in the disease of interest.  

The potential of induced pluripotent stem cells was recognised by Roche more than three years ago and the company has since been working with researchers at Harvard University, Massachusetts General Hospital and Boston Children’s Hospital to create more than 100 human induced pluripotent stem cell lines that can be used to model cardiovascular and neurological diseases. 

STEMBANCC stands as one of IMI’s biggest projects to date, with a total budget of EUR 55.6 million (USD 72.3 million). In its effort to boost drug development, IMI has also launched another six projects, which will focus on data integration and management, drug behaviour in the body, and ‘green’ drug development, amongst others. 

Roche and the Innovative Medicines Initiative (IMI) have recently launched an academic-industry partnership, known as STEMBANCC, under which 10 pharmaceutical companies and 23 academic institutions will collaborate on using stem cell technology to accelerate the development of safer and more effective drugs for patients.

Roche Collaborates on Stem Cell Project

  In your opinion, how successful has the industry been in fighting drug counterfeiting over the past few years? How would you describe the prevalence of the problem today? 

  The situation is totally different depending on where in the world you look. In the EU and US, one would be unlucky to come across a counterfeit medicine. However, as the recent Avastin case (1) showed, even these relatively well-controlled supply chains are vulnerable. In many developing countries, counterfeit drugs constitute a lethal epidemic that is killing thousands of people every year. Most fake drugs are ineffective rather than toxic, and patients still die needlessly from a disease that modern medicine could cure or control because they are taking counterfeits unknowingly. There are no easy answers but there are more things that we could do to help. We need to help these countries to build regulatory capacity, invest in monitoring equipment, educate and involve the end user in the verification process. 

 The problem seems to becoming more prevalent because anticipating where counterfeiting will hit, both geographically and in terms of brand and medicine area, adds to the difficulty. Some have the view that big pharmaceutical companies are more concerned with developing new products and dealing with regulatory issues, and thus, their supply chains are being overlooked. The struggle to encourage a balanced investment in both drug development and supply-chain management can also escalate the problem of counterfeiting. 

  The globalisation of pharmaceutical supply and manufacturing has contributed to the rise in counterfeit medicines. What are some best practices that the industry can apply to secure their supply chains, especially for products coming from emerging markets such as China and India? 

  The key is to examine processes first and then look at security technologies. At Blue Sphere, we use a simple mnemonic called DRASTIC: Define goals, do a Reality check, collate and Analyse data, draw up a Strategy, develop Tactics, plan Implementation, ensure Communication. Many companies make the mistake of jumping to tactics and then getting hung up on technology choice and pack features. Technology bolted on to insecure processes does not add anything except cost. Look at all of your supply chain processes from a counterfeiter’s viewpoint. The right question is not ‘could a criminal copy what we do?’ but ‘could they disrupt, negate, or subvert our processes so that counterfeiting is made possible?’ As a minimum, you should audit all your suppliers for their security processes, as well as the usual product quality parameters. When you are ready to add security features, there are often many free or low cost approaches that you can take. Seek advice and always have a backup plan. Even the best security approaches will eventually be compromised so planned upgrades are a good idea. 

 There are several practices the industry can apply to secure its supply chains. The key ones are: 

Use good distribution practice (GDP) to ensure that products are consistently stored, transported, and handled under suitable conditions throughout a product’s lifetime. 

Apply due diligence, which is crucial to identify potential business issues that may give rise to unexpected liabilities that could have knock-on effects. 

Audit suppliers and contract providers to ensure that they adhere to both national and international standards. 

Incorporate packaging features, such as tamper-evident labeling to demonstrate to end users that the medicine is safe for use. 

 What challenges still exist in terms of coding and tracing drugs reliably and securely through the global supply chain? 

  One key issue for manufacturers is harmonisation of standards. The uncertainty in timing and variation in technical requirements worldwide is adding to the expense faced by manufacturers. Most major manufacturers must plan for multiple legal scenarios. On production lines, which might supply many different geographies, the most onerous coding regime determines the line configuration. An international coding convention would be a major step forward. GS1 standards provide one framework in terms of code formats, but the rules for which transactions need to be recorded and how data are stored and shared also need to be standardised. 

Another key issue is ubiquity. How do we ensure that all countries have access to scanning equipment to check for counterfeits at the borders? There is a strong ‘network effect’ in product traceability—that is, the security of the system increases with the number of transactions that are verified. The logic of this approach is that we should involve developing countries in drug-traceability schemes as well as developed economies. In my view, one way to do this is by using mobile phone technology, which can empower billions of patients. 

 The challenge regarding tracing drugs reliably and securely is that the problem is getting bigger with time. Pharmaceutical companies are working in an international environment, which is hard to moderate due to different regions presenting different challenges. 

Coding and marking go quite a way towards building and operating a secure global supply chain, but need to be supported by other elements, such as risk assessment and management, to create a safe ‘whole supply chain’ picture. 

There also needs to be more investment in technologies that support the coding and marking of drugs. It is ironic that, in most countries, a bottle of water can have more tamper-evident packaging than a £1000-oncology drug. Combining coding and marking with such strategies would be a huge help. 

 What new authentication technologies and system strategies can help to identify and prevent counterfeits? 

  The world is going mobile. It seems logical that this trend should be factored into product security strategies. The pharmaceutical industry still has an obligation to provide a secure supply chain, and there are new ways to enable authentication of codes, such as fingerprinting technologies. The industry must continue to invest in the safety of its supply chain. However, allowing the patient to verify their medicine as an additional last step gives millions of extra eyes and can provide excellent opportunities for data mining to discover patterns of counterfeiting. Consumer verification is proving to be very popular in the developing world. In India, in particular, the approach has been a useful addition to the arsenal of anticounterfeiting approaches. There are no easy answers to counterfeiting. It requires multiple layers of defence, concerted action by industry and constant vigilance by consumers. 

 There are a handful of new authentication technologies and system strategies that can help to identify and prevent counterfeit medicines. A key one is mass serialisation. Although this technology comes with the associated challenge of reliable authentication, it can be highly effective in terms of offering producer to patient traceability and pinpointing risks. Other strategies that can help identify and prevent counterfeits are the inclusion of digital signatures, asymmetric encryption and covert features, which can be verified with a mobile phone. 

1. On Feb. 14, 2012, the media reported that counterfeit versions of Roche’s multibillion cancer drug, Avastin (bevacizumab 400mg/16mL), had been distributed in the United States. 

Blue Sphere Health is a consultancy based in the United Kingdom, with a focus on global healthcare, pharmaceutical security, patient safety and anticounterfeiting. Domino Printing Sciences, a company specialised in coding, marking and printing technologies, formed an internal task force in 2011, dedicated to helping pharmaceutical manufactures comply with the new European Union’s Falsified Medicines Directive (FMD) that member states must begin implementing in Jan. 2, 2013. 

As the battle against counterfeits gains momentum, PharmTech speaks to Mark Davison, CEO of Blue Sphere Health, and Craig Stobie, global life sciences sector manager at Domino Printing Sciences, about the challenges involved.

Tracking the Supply Chain

Counterfeit medicines are prevalent across the globe. From proprietary medicines to generic drugs, counterfeiters are not only targeting lifestyle drugs such as Viagra and Cialis, but also expensive treatments for life-threatening conditions such as cancer. This year saw the appearance of counterfeit Avastin, which affected 19 medical practices in the United States, demonstrating that even countries with stringent regulatory and enforcement systems are not exempt from the escalating problem of counterfeits (1). In this digital age, the Internet provides an easy channel for counterfeiters to dispense their fakes. Purchasing medicines online with just a click of the mouse is becoming increasingly prevalent because of the convenience it offers, and according to the World Health Organization (WHO), constitutes more than 50% of counterfeit cases (2). In July 2011, the European Commission published the Falsified Medicines Directive (FMD) 2011/62/EU in an effort to better protect patients and consumers. The new directive, which aims to prevent falsified medicines from entering the legal supply chain and reaching patients, will come into effect in January 2013. Meanwhile, FDA's Safety and Innovation Act (FDASIA), enforced in July 2012, has made provisions to ensure the safety of drugs, for example by implementing new counterfeiting penalties, including one for trafficking fake medicines. 

To examine the progress made to date in the war against counterfeits, 

 spoke with Lynne Byers, vice-president of quality at GlaxoSmithKline, and Brian Johnson, senior director of supply-chain security at Pfizer. Both are representatives and members of Rx–360, an international pharmaceutical supply chain consortium developed by volunteers from the pharmaceutical and biotech industry, with a mission to protect patient safety by enhancing the security of the pharmaceutical supply chain to assure the quality and authenticity of products and materials moving through the supply chain. 

 How successful have regulators and the pharmaceutical industry been in the battle against counterfeits? 

 We have made great progress as an industry in battling counterfeit medicines and other supply-chain security breaches; however, there is still much more to do. Some examples of positive progress from a legislative perspective include the passing of the FMD in Europe and FDASIA in the US. Operation Pangea is an example of collaborative enforcement efforts, where an international law enforcement campaign involving 100 countries succeeded in shutting down more than 18,000 rogue online pharmacies. Rx–360 has also done some great work in the supply-chain security space, with several white papers that will help prevent, detect, and respond to counterfeiting and other supply-chain security threats. There are many other examples and they all contribute to our fight in different ways. Nevertheless, even with these success stories, we still see examples of global supply-chain security breaches in the news every day. We must remain vigilant. 

 What would you identify as the key provisions on the EU FMD or the US FDASIA in addressing supply-chain security? How can regulators better harmonize efforts globally? 

 In terms of improving supply-chain security, the key provisions of the FMD are as follows. All active substances, or APIs imported into the EU, will be required to be manufactured in compliance with GMP equivalent to those of the EU by Jan. 2, 2013. Written confirmation of compliance with this requirement, which will be issued by an authority in the exporting country, will need to accompany all active substances imported into the EU as of July 2, 2013. Exporting countries may apply for an exemption to these rules, but no country has been granted an exemption to date. In exceptional circumstances, and where necessary to ensure the availability of medicinal products, if the API manufacturing facility has an EU GMP certificate, then a member state may waive the requirement for written confirmation for a period not exceeding the validity of the GMP certificate. Member states that make use of the possibility of such waiver shall communicate this to the European Commission. The first country has just been granted an exemption from the written confirmation requirements—Switzerland. The process, which is to be used by each member state's regulatory authority, has not yet been communicated. In terms of regulators working more closely together, the mutual recognition of inspection reports is encouraged because this will help regulators to inspect more facilities. 

 Collectively, the recent legislation in the US and EU will help enhance supply-chain security but we need similar legislative initiatives in other regions of the world to level the playing field. Our supply chains are complex and global, and because the weakest link is what criminals will exploit, global harmonization is critical. We are heading in the right direction with initiatives by regulators to collaborate on auditing, information sharing, and risk analysis. Other stakeholders are collaborating through organizations such as Pharmaceutical Cargo Security Coalition (PCSC), Pharmaceutical Security Institute (PSI), and Rx–360. It is hard to single out specific provisions of legislation, regulations, or efforts by specific organizations because they all contribute in different ways and attack different aspects of the problem. The key will be continued collaboration and avoiding working in silos, which we tend to do sometimes.  

 Could you provide an update on Rx–360's initiatives and activities thus far in 2012 and its focus of activity for 2013?  

 Firstly, as a consortium, we are enhancing and facilitating joint and shared audits. Both audit programs are operational following a period of piloting. Secondly, we are also addressing a broader range of supply-chain security topics. A new supply-chain security group was established and has developed and shared best practice documents. Thirdly, we are actively engaging regulators and educating legislators. In terms of communications, we have organized webinars around many Rx–360 initiatives. We have also produced 326 news flash reports and process for industry wide messaging, 90 summaries of proposed or passed regulation or legislation with an average time to publish between 6–10 days, 16 newsletters and conducted 4 open meetings.  

For 2013, we have targets to increase membership in all categories and to continue to work on our priorities of the audit programs, supply-chain security and analysis, and swift dissemination of supply-chain security information. 

 To date, what are the three biggest achievements accomplished by Rx–360? 

 I would say that our three biggest achievements are: global collaboration between manufacturers and suppliers within the organization; a positive opinion from the Federal Trade Commission (FTC) that the audit programs, if operated as described to the FTC, are unlikely to breach US anti-trust laws; and our ability to pull together world experts to work on a problem within a tight timeframe (e.g., following the tsunami in Japan). 

 What best practices can you offer for the industry to monitor their materials coming through global supply chains, especially with products coming from emerging markets, such as China and India?  

  Rx–360 develops and shares best practices and points to consider in relation to the security of the supply chain. This ­information is freely available on the Rx–360 website. One example of a point to consider relates to tamper evident seals, which are used on raw material containers (3).  

 Companies need to have comprehensive supplier quality management programs to monitor and manage materials and products from external sources, regardless of the region being sourced from. This starts with supply chain transparency and a good understanding of all of the "players" in the supply chain. When the supply chain is well understood, companies can then use risk-assessment processes to determine appropriate strategies to mitigate risk, including risks associated with sourcing from regions with less developed regulatory infrastructure. Having clear requirements, good contracts, and robust oversight programs to ensure your suppliers meet your expectations are foundational.  

With regards to supply-chain security, what are the common challenges faced in preventing and detecting intentional adulteration, illegal diversion, and counterfeiting of products and packaging? What steps or holistic approach is Rx–360 taking to address these problems considering how complex the pharmaceutical supply chain can be?  

As an industry, our biggest challenge and our greatest opportunity is tackling supply-chain security threats holistically. We have historically organized around individual threats, such as counterfeiting or specific parts of the supply chain, such as contract manufacturing. We also have not always balanced prevention, detection, and response to these threats. Winning this battle will require collaboration across the supply chain and between all stakeholders. 

What we are trying to do in Rx–360 is to promote a holistic approach to supply-chain security. This includes defining the supply chain broadly (end to end), recognizing the advantages of working on the threats (counterfeiting, theft, diversion, and intentional adulteration) collectively, and balancing prevention, detection, and response. Our first whitepaper on comprehensive supply-chain security programs captures many of these concepts and is a good roadmap for the supply-chain security work we will be doing.  

 Could you give some background on the aims and functions of the different supply-chain working groups under Rx–360 and what each working group has achieved to date? 

 Rx–360 endorsed the creation of the supply-chain security working group in October 2011. The goal of this working group was to promote a holistic approach to supply-chain security. We kicked off four working teams towards the end of 2011. The objectives for each of the teams were:  

—Benchmarking and white paper describing comprehensive supply-chain security program. 

—Benchmarking, development of risk model and white paper on using risk- based approaches to conveyance security. 

—Benchmarking, white paper and framework on good practices/tools-techniques, emerging technologies, to monitor the market for criminal activity. 

Audits and Assessments of Third Party LSP's

—Points to Consider for audits/assessments; audit standard methodology; audit tools for LSP's.  

Free webinars were conducted for each workgroup and the whitepapers are currently posted on the Rx–360 website. This was all accomplished in approximately six months. 

We also recently kicked off four additional workgroups with the following objectives:  

—benchmarking and development of a white paper describing a process to respond to supply-chain breaches. 

—benchmarking and development of a white paper on approaches to prevent, detect, and respond to illegal diversion. 

—benchmarking and development of best practices for what companies can do to prevent supply-chain security breaches resulting from drug shortages. 

—discussion group to share information on strategies and challenges for implementing serialization globally. 

 Could you briefly discuss best practices when it comes to responding to supply-chain security breaches?  

 A centralized effective incident management process for intentional adulteration, theft, illegal diversion and counterfeits is important. A comprehensive process should have the following attributes: accurate and timely incident reporting; timely investigation; immediate actions where appropriate (e.g., notifying regulators and law enforcement); risk assessment; identifying root cause if applicable; executing corrective and preventative actions; monitoring, analysing and reviewing trends; and continuous improvement. This is not that dissimilar to the processes we use in our quality management systems. 

 The serialization implementation discussion group aims to get companies to collaborate on implementing differing requirements globally; could you discuss the challenges involved in this process and the steps being taken by Rx–360? 

 First, it is important to point out what Rx–360 is not doing with this discussion group. We are not advocating on the various legislation and/or regulations being developed globally. There are other organizations actively engaged where our member companies participate so we decided to focus on an unmet need, which was to create a forum where supply-chain stakeholders could share information and approaches being taken to implement solutions and make investments (e.g., technical and IT) in a world where significantly different models are being developed. The challenges are obvious when we all work in a global marketplace.  

 is vice president of quality at GlaxoSmithKline. 

 is senior director of supply- chain security at Pfizer. 

 1. FDA, "Counterfeit Version of Avastin in US Distribution" (FDA website, 2012)., accessed Nov. 12, 2012.  

 2.  WHO,  "Medicines: spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines" (WHO website, 2012), accessed Nov. 12, 2012.  

 3.  Rx–360, "Rx–360 Points-to-Consider: Optimizing Pharmaceutical Raw Material Tamper Evidence" (Rx –360 website, 2012), accessed Nov. 12, 2012.  

Adeline Siew PharmTech speaks to Lynne Byers and Brian Johnson about Rx-360's initiatives to protect patient safety.