How to secure product brand integrity with integrated protection strategies

A presentation from Dr. Edgar Mentrup der Merz Group Services GmbH

- Background information
- Technologies to prevent/detect counterfeits
- Integrating approaches, cost effective
- How do others manage?

Definition of WHO:
“a medicine, which is deliberately and fraudulently mislabelled with respect to identity and/or source.
 Counterfeiting can apply to both branded and generic products and counterfeit products may include products

• with the correct ingredients or
• with the wrong ingredients,
• without active ingredients,
• with insufficient active ingredients or
• with fake packaging”.

Actual situation (US)
2008 seizures totaled more than $272.7 million in counterfeit and pirated goods, an increase of 38 percent over the previous year

Product-recalls in UK due to counterfeits

Lipitor Tablets (Pfizer) 2005
– Tablets contain lovastatin as opposed to Atorvastatin
– Recall of 120,000 packs - 73 packs of counterfeit drug seized
Casodex Tablets 50 mg
– Bicalutamide, Astra Zeneca, June 2007:
– Parallel import. Contains about 75% of the active ingredient
Plavix Tablets 75 mg
– Clopidogrel, Sanofi-Aventis & Bristol Myers Squibb, May 2007:
– Parallel import. Contains 70 - 80% of the active ingredient

Technology – requirements

- Economics (depending on product, price, margin, ..)
- Authentication (Quality,speed)
 • Patient/consumer
 • Pharmacists / doctors (professionals)
 • Company associates (selected)
 • Officials (police, customs, investigators)
- No or minimal impact on productivity (line speed,..)
- Risk of imitation/Quality of protection (duration before replication)
- Integration into company workflow (order, handling, ..)
- Flexibility / options for changes (costs & communication !)
- Forensic validation of marker fingerprints for legal action

Protection measures - differentiation

Covert / high level

• Only visible to trained staff
• Most often special equipment required
• Very difficult/impossible to replicate

Cover / low level

• Visible to trained staff
• No special equipment required
• (only e.g. UV light)

Overt

• Visible to everybody (e.g. color)
• No special equipment required
• Communication to customer required
• Risc for replication requires regular updating

 

Identifying the product itself

Raw materials– API to identify the source of material and understand chain
  e.g. specific pattern of related substances
– Addition of markers/tracers

Printing / Embossing– Nano-technologies
– 2D Codes
– On-tablet laser inscription technique, DataLase Pharmamark(TM).

Film coatings includes an additive that induces a color change in
the film coating precisely at locations on the tablet surface exposed
to a low-power CO2 laser. Identification control of every single
tablet.

Special coating of solid dose forms ...

To view all details of this presentation, download the PDF now: Global Pharma Authentication and Counterfeiting.

(c) Dr. Edgar Mentrup, Merz Group Services GmbH, 2009

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EU herbal medicines law set for legal challenge

An EU ban on unregistered herbal medicine will be difficult to implement fairly and is set to be challenged in the courts, campaigners have claimed in advance of an impending deadline for the sector.

 

On 1 May the EU's Traditional Herbal Medicinal Products Directive – first passed in 2004 – will come into full effect, compelling herbalists to conform to new registered standards.

The initiative affects manufactured products sold online or in shops without the supervision of a practitioner. From May onwards the distribution and purchase of such unregistered medicinal herbal remedies will become illegal.

Campaigners for the industry are set to challenge the full introduction of the directive and claim that member states are adopting varying standards to its implementation.

Dr. Robert Verkerk, executive and scientific director of the UK-based Alliance for Natural Health – an NGO promoting natural remedies – said: "At the end of April we plan to challenge the directive first of all in the High Court in London, on the grounds that it is disproportionate, non-transparent and discriminatory. We then hope to have the case referred to the European Court of Justice in Luxembourg."

Verkerk said that countries such as the Czech Republic and the Netherlands were adopting a liberal approach to implementation which meant that many herbal remedies could be construed as ordinary foodstuffs and thus escape regulation.

He added that other states, notably the UK and Belgium, were approaching the directive more vigorously, outlawing many more unregistered herbal remedies.

In defence of natural medicine
Meanwhile in France a petition against the directive has been launched by a group of natural remedy stakeholders calling itself 'Le Collectif pour la Défense de la Médecine Naturelle'.

It also complains of the variety of different approaches taken in member states and claims the directive imposes a disproportionately costly administrative burden on numerous natural remedies which have existed in Europe for centuries and are not dangerous. A statement from the campaign said: "We simply want the right to treat ourselves using alternative methods."

Examples of remedies threatened following the expiry of the deadline include traditional European herbal cures using hawthorn and meadowsweet in addition to a swathe of herbs used in traditional Indian Ayurvedic, Chinese and Amazonian remedies.

Exact data on the use of herbal medicines is scarce. However, an influential US-based medical journal, the New England Journal of Medicine, estimated that in 2003 European countries spent almost €3.5 billion (at manufacturers' prices to wholesalers) on over-the-counter herbal medicines.

Positions

Dr Robert Verkerk, executive and scientific director of the UK-based Alliance for Natural Health, said: "The problem is that [synthetic chemical ingredients] are deemed necessary by formulators in order to meet the pharmaceutical stability standards set by the EU directive. Forcing non-European herbal traditions into a European straitjacket would effectively corrupt these great traditions."

"A new, more appropriate and affordable system of quality control is urgently required to prevent discrimination against the long-standing traditions, and this is something we aim to push for through our planned judicial review," Verkerk said.

A spokesman for the Association of the European Self Medication Industry, which represents the manufacturers of non-prescription medicines, said: "We have heard that among some of the smaller companies that manufacture these remedies there may be some difficulties with the new rules. However there has been a very long transitional period pending the introduction of the full directive and we do not disagree fundamentally with the directive itself."

Irish liberal MEP Marian Harkin, who is a member of the NGO Health First Europe, said: "There are real concerns that many of these herbal remedies will not be available to the public anymore. Many have been in use for thousands of years. There are issues about how they are to be assessed: can you use pharmaceutical techniques to assess something that is not a pharmaceutical product? A lot of these remedies will disappear."

A spokesperson for Le Collectif pour la Défense de la Médecine Naturelle said: "If charlatans exist within the sector, that does not justify the persecution of those who rely on numerous producers of plant-based alternative therapies. This type of vigilance will only benefit those who are able to verify that their medicaments are manufactured using certain petrochemical compounds, from which the  side effects are incontestably worse."

Czech Socialists & Democrats MEP Pavel Poc said: "It is not acceptable that a directive which originally aimed at safe use of traditional Asian medicines doesn't allow registration of even a single Ajurveda or Traditional Chinese medicinal product. Yet, this is exactly the situation in the Czech Republic and according to our information also the case in other countries of the EU. If the product doesn't fit into a food supplement category its sale becomes illegal. I'm now considering further options how to prevent such a scenario."

Background

The Traditional Herbal Medicinal Products Directive, 2004/24/EC, was established to provide a regulatory approval process for herbal medicines in the EU, and came into force on 30 April 2004. Under the regulation, all herbal medicinal products are required to obtain an authorisation to market within the EU.

Those products marketed before this legislation came into force can continue to market their product until 30 April 2011, under the transitional measures defined in the directive. Once this time limit has expired, all herbal medicinal products must have prior authorisation before they can be marketed in the EU.

Under the directive, a company needs to demonstrate the safety and efficacy of its herbal medicine through traditional use within the EU for at least 30 years, or 15 years within the EU and 30 years outside the EU.
The intended use of a herbal medicine will only be authorised on the basis of its traditional history and/or the recognised pharmacological properties of the herbal ingredients.

More on this topic

LinksDossier:Health literacy: Unlocking patients' potential

LinksDossier:Medicines in emerging markets

Next Steps

• 1 May 2011: Full implementation of the directive comes into force.

Links

EU official documents

• Eur-Lex Directive on traditional herbal medicinal products (31 March 2004) [FR] [DE]

NGOs and Think-Tanks

• The Herb Society: A Guide To The EU Traditional Herbal Medicines And Its Possible Implications Directive 

Source: (c) Euractiv

Just how big is Pharma? A view on the US market.

According to the OCED, 2008 saw four of the five largest pharmaceutical companies increase their total revenue coming from the US market bymore than 30 percent. For Johnson & Johnson, that figure leapfrogs to 53 percent (excluding consumer products), while Pfizer's US revenue accounts for 41 percent of its total last year. GSK sees the figure falling at 38 percent, while Sanofi-Aventis is positioned at 31 percent. Just behind, Bayer still managed to accumulate 28 percent of total revenue for 2008 from the US market.

These figures found its way into a blog-post by McArdle and even though the original figures published were somewhat controversial and exaggerated the main concern that blog post raised at the time is still very valid.

Take for instance the massive $10.4 billion profit GSK experiencedin 2008 , or the $8 billion raised by Pfizer, which is now recognized as the world's largest pharmaceutical company following its merger with key rival Wyeth. These figures are massive by anyone's standards. As such, the pharmaceutical industry, which has largely weathered the economic crisis in comparison to other sectors, is fast being refered to as "too big to fail".

This tag was last applied to the financial services industry before the recession hit and the bailout began.

While it seems McArdle's online post might stick around in blog-readers' minds for all the wrong reasons, a look at the statistics behind the furore is certainly worthwhile. Big Pharma might be big, there can be no denying that; but too big? Well, we'll let you make up your own mind. Take a look at this infographic.

Click on the graphic to view a larger version.

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The Stats about Pharmaceutical Companies....

Online Colleges and Universities made up the following infographic on pharmaceutical companies in the US. This is a really interesting one. Toview a larger version, click on the image.

Source: Online Colleges and Universities

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Operational Excellence and Demand-Driven Manufacturing

In this great report Alfred Sherk is examing Operational Excellence and demand-driven manufacturing.

Operational Excellence and Demand-Driven Manufacturing

The pharmaceutical industry is facing enormous pricing pressure around the world and it is especially intense in the United States as drug costs are a significant part of the debate on healthcare reform. The leading pharmaceutical companies understand the long term consequences to their industry. Even more troubling, a recent McKinsey & Co. analysis of the pharmaceutical industry, estimates that “the internal rate of return (IRR) on small-molecule R&D is now around 7.5%, which is less than the industry's cost of capital”1 Consequently, operational excellence has become a key component of their business strategies to ensure their long term vitality.

Operational excellence, stated simply, is minimizing waste while maximizing customer value. Value is defined from the perspective of both the external and internal customer in a measurable manner. The Lean movement has developed important key performance indicators for measuring an operation’s performance and bench marking its performance against the achievements of best-in-class organizations.

According to Womack and Jones, there are seven types of process waste – rework, overproduction, excess inventories, non-value added process steps, excess people movement, excess material transportation, waiting, and non-value added goods of services. In the pharmaceutical industry, waiting and excess inventory are significant sources of process waste and often mask underlying work process deficiencies.

A common pharmaceutical practice is to plan global distribution requirements 90 days in advance and carry significant inventory levels to protect service. Since the value and importance of its products is very high, protecting high service levels at the point of consumption is a necessity. Nevertheless, the median inventory turn, industry wide, is just 3.4 turns2. The time that it takes to move from end-to-end consumes a substantial portion of the product’s shelf life. Furthermore, as competitive product substitution is an inherent aspect of the generic market, more responsive suppliers gain competitive advantage.

Access the full report and download the free PDF now: Operational Excellence by Alfred Sherk

End-to-end Throughput Time

Reducing the overall throughput time from end-to-end, from the first chemical reaction all the way through distribution, improves market responsiveness, reduces risk through less exposure time and improves profitability. Just as importantly, from an operational excellence perspective, it exposes inefficient or even incapable processes that are masked by high inventories and long lead times. 

Novartis’ continuous manufacturing paradigm, a component of their Lean program, has led to the reduction of their overall throughput time from 550 days to 200 days for some of their major products and they see the opportunity to get it to just 1 month3.

In the pharmaceutical industry there are three main challenges to operational excellence: demand visibility, collaboration and determining the right operational response. On the surface, these items would appear to be straightforward to address but are in fact very difficult due to the complexity of the total order-to-fulfillment process.

Read the full report here.

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The European Parliament has approved the falsified medicines directive and described it as a “huge step” in efforts to protect patients.

"Falsified medicines are silent killers, either because they are devoid of effect or because they contain toxic substances that may harm, or even kill, those who take them”  -- Marisa Matias

Development of the directive has taken several years but in February the European Parliament quickly, and overwhelmingly, approved the document that was in final draft mode since April 2010. Despite some misgivings, speakers in Parliament were very supportive of the directive and the safety benefits for European patients.

Marisa Matias, a member of the European Parliament (MEP) took a key role in drafting the directive says: "Falsified medicines are silent killers, either because they are devoid of effect or because they contain toxic substances that may harm, or even kill, those who take them”

Now, with a legal framework, recognising the falsification of medicines as a crime, in place and preventative measures in the pipeline Matias, and other MEPs, believe a “huge step” has been taken.

Industry response
 
The Pharma Industry is also broadly supportive of the new directive. Brian Ager, director general of the European Federation of Pharmaceutical Industries and Associations (EFPIA), welcomed the directive and called on all key stakeholders to commit to making it a success.

Others, while welcoming the directive, raised concerns about the specifics. For instance, the European Generic medicines Association (EGA) called on the Commission to adopt a risk-based approach to avoid placing “unnecessary burden on low risk products, such as generic medicines”.


The Pharmaceutical Group of the European Union (PGEU) also has concerns about details the Commission is still to determine, in particular the electronic verification system. PGEU will work with the Commission to ensure the verification system is comprehensive and efficient.

Is the new directive going far enough?
 
MEP concerns in the pre-vote debate focused on whether the directive is bold enough or too much of a compromise. Internet sales, inspections of ingredient suppliers outside the European Union and traceability were three areas in which some MEPs wanted stronger measures.

For instance, Amalia Sartori, an MEP who authored an opinion on the directive, said the final document fails to cover some of the fundamentals, such as mandatory overseas inspections. Matias has also sought mandatory inspections but others felt it was unviable.

John Dalli, the European Commissioner for Health and Consumer Policy, said the quantities of ingredients coming from overseas make it impractical to inspect all sites. Instead Europe must cooperate with nations that have high quality standards and conduct risk-based inspections.

APIC response
 
The directive “is a major step forward”, Chris Oldenhof, president of APIC (Active Pharmaceutical Ingredients Committee), told in-PharmaTechnologist. APIC called for mandatory inspections but believes the combination of a number of initiatives may be sufficient.

In recent years the focus on API issues has “dramatically increased”, said Oldenhof, and joint inspections, Medicrime, Rx-360 and draft drug safety legislation in the US could all contribute to quality.

To read the full draft legislation against falsified medicines, click here: Global Pharma Authenication - EU Legislation against falsified medicines.

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Drug transporters and their role in drug interactions and toxicity

Background

Drug transporters have gained prominent attention from almost everyone involved in drug development across the globe in the last two decades. Researchers now have a fair understanding of the vital role played by drug transporters in drug absorption, distribution, metabolism and excretion (ADME). Attention has been drawn towards their involvement in drug interactions and toxicity. Improvement in clinical translation of in vitro and preclinical transport studies and increased impact of regulatory authorities for better understanding of transport interactions (draft EMEA guidance and 2010 ITC whitepaper) are also stressed.

A range of various drug transporters is present in the human body. Most important of these include transporters expressed particularly in the endothelium of the blood–brain barrier and in the epithelia of the liver, intestine, and kidney during drug development. These drug transporters are specific to their substrates. However, the number of substrates specific to each transporter may vary. For example, a transporter may be specific for only one substrate while another may act as a transporter for three substrates. At a particular site,  distribution of each of these transporters varies, entailing the different physiological functions and sometimes the pathological reaction. Lack or absence of these transporters can result in numerous genetic disorders. The bioavailability of drugs with less permeability and absorption can be enhanced by the use of transporters involved in the absorption or else by restricting the transporters required for the efflux system.

Thanks to fresh developments in molecular biology in gene cloning and other techniques, molecular level characteristics and distribution of transporters can be studied. Over the years, the major cause of failure for late stage therapeutic entities during drug development has been drug-induced organ toxicity. In vitro screening of molecular compounds can be done to ascertain the effect of drugs on various pathways or mechanisms that might be linked to drug toxicity. However, very few negative in vivo outcomes can be predicted in this manner; as in the case for most of the models, the in vivo conditions cannot be replicated.

The two major conditions required to determine the organ specificity for toxicity are increasing the concentration and delivery of drugs to the target. Much progress has already been made in deducing the role of these drug transporters in drug safety and efficacy. For the human genome, over hundreds of transporters have been discovered. Examples include the two most important superfamilies, namely, the ATP binding cassette and the solute carrier (abbreviated as ABC and SLC, respectively).


Since a lot of research has been done with focus on interaction of drugs and their metabolites, scientists have simultaneously developed a huge range of literature on the topic. Several of these studies suggest the in vivo role of drug transporters in the drug’s disposition, efficacy and some negative responses. Models for in vivo demonstration of the role of drug transporters include a number of animal species, commonly knockout (KO) mice. In humans, loss-of-function genetic variants have also been used. The in vivo role of many ABC and SLC transporters has been elucidated using such studies. Many such studies have proved the role of  transporters along with several drug-metabolizing enzymes (DMEs) during ADME. Clinical pharmacokinetic drug-drug interaction studies also support genetic polymorphism of DMEs.

Read more about:

    Overview of drug transporters:

• P glycoprotein (P-gp)
• BCRP
• OCTs and OATs
• OATPs

1. Issues on Drug Development
2. Future Directions
3. Conclusion

Click here for the complimentary 5-page article: Drug Transporters.

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