Wake-up Call - Infant formula laced with melamine, heparin tainted with oversulfated chondroitin sulfate, cough syrup contaminated with diethylene glycol - these scandals didn't just cause outrage among consumers over the recent years. They have also served as a wake-up call for both suppliers and manufacturers in the pharmaceutical industry and have made apparent the need for companies on both sides to work together to exchange information.

Industry initiatives such as the European Fine Chemicals Group (EFCG) and the International Pharmaceutical Excipient Council (IPEC) as well as a new international pharmaceutical supply chain consortium Rx-360 are dedicated to help to overcome this challenge. Rx-360 was launched in January 2009 with the aim of enhancing the security of the pharmaceutical supply chain and to assure the quality and authenticity of the products moving through the supply chain.

Brandi Schuster spoke with Dr. Najib Sehat, Head of Regulatory Service at Merck's KGaA newly created Merck Millipore division and the company's Rx-360 representative, about the work the group has done and the inherent problems that exist when it comes to regulating excipients.

CHEManager Europe: Dr. Sehat, what is the difference between Rx-360 and other organizations already out there?

N. Sehat: The uniqueness of Rx-360 is that pharmaceutical and biotech industries, as well as their suppliers, are globally working under one roof with the aim to improve the supply chain - from APIs all the way to packaging materials - and to set standards for the improvement of quality. This collaborative effort will enable the industry to avoid the tragic situations that we have unfortunately seen in recent years. The main focus is on the patients' health and safety.

How has industry interest been in the organization?

N. Sehat: After the successful launch of the organization in at the beginning of 2009, Rx-360 was incorporated as a non-profit consortium to support an industry-wide commitment to help ensure patient safety by enhancing quality and authenticity throughout the supply chain.
The first Rx-360 global open meeting took place at the Merck KGaA headquarters in Darmstadt, Germany, in September, with 125 global attendees, representing some 89 organizations from across pharmaceutical, biotechnology and generic drug manufacturing industries, along with their suppliers, professional trade associations and regulatory agencies, including the U.S. Food and Drug Administration , the European Medicines Agency and the European Directorate for the Quality of Medicines & HealthCare.

Approximately half of those in attendance were from organizations that are considering joining the 51 organizations that already make up the Rx-360 consortium. Attendees came to the open meeting to hear from regulators and learn about the consortium's tremendous progress in the past year and future plans. There has been a very positive industry response to this consortium.
Our aim is to hold this kind of open meeting once a year; next year's is planned to take place in the U.S. in May.

How does Rx-360 work together with other organizations, such as the EFCG or IPEC?

N. Sehat: At this stage, eight associations have an observer status within Rx-360, including the EFCG and IPEC. An observer is able to participate in certain Rx-360 activities and receives quarterly updates on all consortium activities. Rx-360 values its collaboration with EFCG and IPEC greatly and has stated from the beginning that the consortium does not want to duplicate existing efforts.

One of the aims of Rx-360 is to endorse or even create standards, if needed. For example, IPEC and its partner organizations have created a set of standards for excipients, such as GMP and GDP that manufacturing authorization holders can use to gauge the suitability of excipient suppliers. After consultation and agreement of IPEC and its partner organizations, the GMP standard for excipients has been endorsed by Rx-360. In order to solve the complex problems that impact the pharmaceutical supply chain, it is tremendously important to intensify the collaboration between all associations and other involved parties.

The U.S. FDA doesn't have an active program to assess excipients. What is Rx-360's take on that position?

N. Sehat: That is correct that excipients are not as strongly regulated worldwide as APIs. In recent years, the excipients market and related requirements have changed dramatically. Certainly this will trigger changes in the regulatory environment. One of the value propositions of Rx-360 is that regulatory bodies will benefit from the improved security and quality, which will allow them to focus their limited resources on other areas that create public health risk.

So there's no frustration on the part of groups such as yours that the FDA is sort of taking a back seat on excipients, letting industry-organized groups take the reins how its products - in the case of excipients - should be regulated?

N. Sehat: Well, the government can't be expected to regulate everything. The new strategy of the FDA is to really emphasize that the real responsibility lies with the manufacturer. Manufacturers are obligated to ensure the quality of their suppliers and they are also obligated to endorse their own quality systems. That's why the FDA proactively asks members of the pharmaceutical manufacturing industry to physically audit the quality systems of their suppliers in the excipient business. Not only that, the FDA clearly states that manufacturers also have quality assurance contracts that share the burden of liability with the supplier side.

Is there an expectation that FDA should regulate excipients?

N. Sehat: An appropriate GMP for excipients would be the right direction. Generally speaking, creating regulation is not a real challenge, but the major challenge would be the enforcement of this in such a global market. The FDA started broadening the scope of the cGMP. In recent years FDA announced a significant new initiative "cGMPs for the 21st Century" intended to modernize FDA's regulations on pharmaceutical quality. The intent of the original initiative was to offer the industry the necessary tools to provide more post-approval flexibility, making continual improvement less of a regulatory burden, and to promote better self-regulation to improve regulatory compliance status. The implementation of the envisioned new framework and its elements require the use of risk-based and science-based approaches for regulatory decision-making throughout the entire life cycle of the product.

Is it possible for companies to properly regulate themselves as far as excipients should go? Shouldn't government play at least a small but active role?

N. Sehat: The industry itself began creating standards for excipients several years ago. As I mentioned earlier, IPEC and PQG created important standards that are well accepted by industries and regulators. One additional important step is the planned Excipients Certification Scheme from IPEC, EFCG, PQG and the FECC in order to establish common acceptable standards to improve excipients quality and patients' safety.

On the other hand, regulators in the EU in 2006 began an effort to regulate excipients, and the European Commission was obliged to bring forward proposals for the application of GMP standards to certain excipients, a list of which was to be defined. The application of GMP standards for certain excipients through legislation has subsequently been considered and discussed by DG Enterprise and interested parties. The decision was made based on public consultation and results were provided in the EU Excipients Impact Assessment Report in 2007. The report underlined clearly that in all cases the expected costs of the possible new policies are much greater than the benefits.

Currently, the EU includes excipients in the scope of the amendment of EU Directive 2001/83/EC, which is its proposal for a directive on falsified medicinal products. In this context, it is clearly noted that in order to provide for a high level of protection of public health, the manufacture of excipients should also be subject to appropriate GMP irrespective of where the excipients were manufactured in the EU or imported. For any medicinal product, excipients should be identified by the manufacturing authorization holder on the basis of an approach assessing the risk caused by the excipients in the medicinal product.

What has Merck done specifically?

N. Sehat: Merck as a pharmaceutical and fine chemical company has been committed to the high quality and safety of its products throughout its history since 1668. Today, as a trusted partner of Rx-360, IPEC, EFCG, etc., we are continuing this commitment to the improvement and enhancement of our state-of-the-art quality management system, always with the benefit of customers and patients in mind.

We are committed to be an active member of the above mentioned organisations and will bring both its expertise and resources to contribute to a global quality system to assure patients' safety and meet pharmaceutical industries' needs and regulatory requirements. Merck foresaw the need and requirement for the excipients in a fast-changing regulatory environment several years ago and launched its Emprove brand pharmaceutical raw materials product portfolio. This brand combines a high quality product with use-related and tailor made documentation.

What do EU manufacturers think about the current market, which is flooded by low quality products from China and India?

N. Sehat: My assumption is that the manufacturers of excipients in Europe do not have a problem with competition from outside Europe. What they want is a level playing field - that means the same competitive conditions and quality requirements independent of where excipients have been manufactured. The aim must be that the same quality and standards should the basis of obtaining safe medicinal products for the consumer

Where exactly does Rx-360 fit into this equation? When one looks over your member list, you've got the big Western players who truly have a vested interest in safe excipients. Aren't you just preaching to the congregation, considering that the real problem seems to be coming from Asia in terms of questionable excipients?

N. Sehat: In Asia, you have to differentiate between suppliers who have high quality and the so-called garage industry, which do business with companies, only to suddenly disappear from the market in the blink of an eye. Generally speaking, we are starting to see quality products coming out of China, but the aim of Rx-360 is to share information among our members.

One of the primary aims of Rx-360 is to share information among members. This will help to ensure that members are sourcing excipients of high quality. One of the goals of Rx-360 in 2011 is also to intensify the activity between all stake holders in Asia and increase the awareness in this important region of the world. Aim is to have the same standard and requirement in place, regardless where the products are manufactured or originated from.

It's clear that many low-grade excipients that make their way into Europe come from Asia, yet the market there is booming. How can companies take advantage of the Asian market without compromising safety?

N. Sehat: It is possible to source high-quality products from China and elsewhere as long as the original manufacturer complies with the required high standards. It is important to note that the pharmaceutical manufacturers should qualify the supplier according to their company standards.
High quality has always its price! I remember a FDA employee once saying that any ingredient is at risk if there is a willing buyer more interested in obtaining the lowest cost ingredients rather than insisting on quality ingredients and insuring their integrity has been preserved throughout the supply chain. Most pharmaceutical ingredient safety problems have been due to a lack of good supply chain control throughout the entire distribution chain from the manufacturer to the user!
This clearly underlines the situation.

Does Rx-360 see itself has having the responsibility to inform companies - both members and non-members alike - on these kinds of issues?

N. Sehat: We see ourselves as having the responsibility to both inform and educate. The problems that we have within the excipient supply chain cannot be solved by just the supplier or manufacturer. As I mentioned before, the uniqueness of Rx-360 is that it brings both sides together under one roof with the aim to improve the supply chain. If both sides put forth enough effort to improve quality and to exchange information in a transparent manner, then the situation could be improved dramatically.

This calls for a high level of trust between your members, who are often also direct competitors.

N. Sehat: When we first began working together in this consortium, some of the members were concerned about this. Rx-360 has made the effort from the very beginning to ensure all activities would be done in accordance with anti-trust laws in the U.S. and anti-competition laws in Europe. Rx-360 has been very careful to build a framework which meets these requirements. In July, Rx-360 submitted information about the consortium activities to the U.S. Federal Trade Commission to seek an advisory opinion on the activities of the consortium. During our open meeting in September, we were thrilled to announce that we received a positive advisory opinion which allows us, to commence the audit sharing program.
It's true a high level of trust is needed among the members, but members realize this is necessary in order to achieve our common mission across industry - to serve patients.

How much progress has been made on this front?

N. Sehat: If we look back five years ago, this intensive exchange of information and cooperation between suppliers and manufacturers didn't exist. No one knew for sure where the products were coming from. The recent scandals, such as the melamine found in infant formula or tainted heparin - both of which cost many people their lives - made the industry wake up and really served as the catalyst for working together. Manufacturers wanted to know exactly where the products were coming from, and we are on a good path to intensify these relationships.

A supplier's role is no longer just to provide a product. Nowadays, we are moving toward having a much more intensified cooperation and transparent exchange of information based on intended use. As a supplier, if we know exactly what the manufacturer's intended use for a particular excipient is, we are able to provide a much higher level of service. If this doesn't exist, it makes working together very difficult. Intensive cooperation between suppliers and manufacturers is absolutely decisive in this business.
Transparency is not just a one way street!

And has this really helped to improve the quality of excipients?

N. Sehat: Absolutely.

What problems still exist within the excipients market?

N. Sehat: The major aspect is the security and integrity of the supply chain. It is essential to have information of the entire supply chain. There is a lack of information here, and this is what needs to be worked on going forward. Rx-360 and other organizations are working very hard on this. Of course, a lot of work still has to be done on the manufacturer and supplier sides as well.

However, I am certain that all of the industry initiatives and activities are going in the right direction and can help improve the quality of medicinal products, in which excipients play also a major role. At the same time, we are seeing new excipients regulatory developments in 2010 within the framework of Directive 2001/83/EC in Europe fighting falsified medicines. For the first time, the appropriate GMP aspects for excipients are highlighted. Based on the new proposal, the manufacturer of medicinal products should ensure that the excipients are suitable for use in their medicinal products by applying the appropriate GMP on the basis of formalized risk assessment in accordance with the applicable guidelines. The final voting is expected in EU parliament in January.

All these and new future challenges can only be overcome if all involved parties work together with the aim to assure patient safety by enhancing product quality and authenticity throughout the supply chain. Patient safety must never be compromised as a competitive advantage.