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EXTRA RISKIn the world of pharma ingredients it is most often the extra, non-active parts that create the highest risk to consumer safety. Dr Arnulf Heubner of the EFCG tells Steve Coomber why regulation needs to focus on the production of excipients to reduce toxicity.

In 2007, certain brands of toothpaste containing diethylene glycol, a chemical used in antifreeze, rather than the intended thickening agent, glycerine,

were discovered on sale in a number of countries. More recently, in 2009, proceedings were brought against Rid Pharmaceutical Company in Bangladesh, for allegedly supplying poisonous paracetamol syrup containing diethylene glycol.

These are just two examples of a number of incidents involving toxic chemicals in a variety of products, highlighting the problems presented by having a truly global market for the production of excipients – the chemicals that make up the majority of most medicines.

That is why Dr Arnulf Heubner, chairman of the European Fine Chemicals Group’s (EFCG) Pharmaceuticals Business Committee and a senior director at Merck, and many others in the fine chemicals and pharmaceutical industry, are arguing for far stronger regulation and for certification of excipients.

‘If you look at a classical medicine, in most cases a maximum of roughly 0.1–10% of it is active pharmaceutical ingredient,’ says Heubner. ’Excipients are those ingredients that are not active. They usually make up more than 90% of the tablet. There are a number of different excipient types – coatings, colours, carriers, fillers, binders, disintegrants, solubilisers, sweeteners and so on – that offer a number of different functions. In the case of coatings, for example, they can control where in the body and when the active ingredient is released.’

The excipients market is highly fragmented, says Heubner, product and production wise. There are thousands of excipient producers in the world, yet none of them, not even the larger firms, has a market share of more than 5%. Nobody dominates the market.

A lack of regulationThe freedom for all to produce and sell excipients in the global market inevitably means that there is pressure on certain producers to cut corners and to compromise

quality by using unsafe chemicals and production processes. In most industries, governance by a programme of standards and regulations, plus enforcement, is ensuring quality and eliminating poor manufacturing processes, but this is still not the case for excipients.

‘The problem was the lack of standard for excipients production,’ says Heubner. ‘There is just the pharmacopoeia, which is nothing more than a description of chemicals from the specifications point of view, including the required analytical methods to test for compliance with these specifications. Only limited general data on impurities is provided based on a variety of different production processes used. Today we know that is not possible to test quality into a product. To ensure quality and safety it is necessary to know and control the manufacturing process

C o n t r i b u t o r p r o f i l e

Dr Arnulf Heubner is responsible for the global business of pharma raw materials at Merck. He is Member of the Board of the European Fine Chemicals Group (sector group of Cefic) and Chairman of the Pharmaceutical Business Committee.

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very well. There is, however, no definition of how excipients should be produced; such standards need to be defined to ensure the quality, safety and efficacy of the final medicinal product at the end of the production process.’

Indeed it seems strange that the active ingredients in medicines are regulated by the EC Directive 2001/83 in Europe on the basis of ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, yet excipients that make up the vast majority of many pharmaceutical products have not been regulated in a way that comes anywhere near to that.

Fortunately for patients and consumers this is where the EFCG stepped in. The EFCG is one of 100+ sector groups in the chemical producer industry. There are over 40 European chemical producer member companies – the producers of APIs and excipients for the pharmaceutical industry – and a board comprised of eight representatives drawn from the member companies. Within EFCG there are a number of committees and task forces. Heubner is chairman of the Pharmaceutical Business Committee within the EFCG.

Before dealing with excipients it made sense to deal with the active ingredients first and ensure their quality of

production. So the EFCG is also pressing for certification and regulation of the production of APIs, and has made significant progress on this, although there are still important issues to be resolved, explains Heubner.

‘In the case of the active ingredients we have a two-pronged approach,’ he says. ‘On one hand we have the competent authorities that are doing their inspections, and on the other hand we have the industry self-regulation fulfilled through industry audits. So this is the model used to ensure the safety of the final drug from an active ingredients perspective, by delivering on both sides.’

At present, however, the problem in Europe with the manufacturing of APIs, especially with off-patent products is that one part of the two-pronged approach is still not fulfilled adequately. As far as worldwide inspection and enforcement by the competent authorities is concerned, this is still not performed in a satisfactory way by European authorities, notes Heubner.

‘There are only a few inspections conducted outside of Europe and the US,’ he says. ‘The Food and Drug Administration (FDA) in the US announced on 28 August 2009 that it will double its foreign Good Manufacturing Practices (GMP) inspections this year. This means that it will do 100, instead of 50 inspections overseas. While this is a good and welcome sign of intent, bearing in mind the many hundreds of producers in higher

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risk areas such as India and China, it is clear that more efforts are needed and that Europe should also step in to achieve a complete coverage of all manufacturers by the API inspection programmes.’

Assuring excipient safetyDespite these shortcomings, having made progress on APIs, in 2007 the EFCG turned its attention to excipients by producing a position paper setting out the case for creating certifiable standards for the excipients used in pharmaceutical products.

With excipients, says Heubner, the situation at present is that there is effectively only one column of regulation in place. There is only a commitment to industry self-regulation. So at Merck there are 60–70 audits per year conducted on excipients, for example. A reliance on self-regulation clearly leaves plenty of room for abuse of the system by unscrupulous or negligent producers.

Heubner and the EFCG want the competent authorities to play a role in ensuring the quality of excipients, in the same way that they are starting to with active ingredients. In drafting terms this would be simple, says Heubner, by merely broadening the scope of the existing European directives covering APIs by adding a number of words in a

certain paragraph, thereby extending the directives to include excipients as well. Creating effective mechanisms to ensure the safety of excipients for consumers needs more work in practice. Establishing a third-party certification system of excipient suppliers is a complex task.

The issue of excipient classification is a challenge, for example, given that the list of purposes for which excipients are used, as defined in international pharmacopoeias, is a very long one. In the 2007 position paper the EFCG proposed a three-tier classification of excipients: common excipients; specific excipients; and novel excipients.

‘A vast majority of excipients are already in use, some for hundreds of years, such as citric acid, the sugars and so on, used for nutrition applications. For these excipients, where we feel the gap to pharmaceutical regulation is not that big, these are what we call “common excipients”,’ says Heubner.

Classification is a challenge – the list of purposes for which excipients are used is a long one.

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’However, with more modern excipients like synthetic polymers, if there are already toxicity problems with the corresponding synthetic monomers, then you will have problem with the safety of the final excipient. So you need a better qualification and validation of processes in order to get a pure substance.’ Fully synthetic polymers, as well as some other excipients such as biologically derived excipients, sterile excipients, or excipients with a known track record of toxic contamination, would be classified as ‘specific excipients’.

Finally, there are those excipients considered to be new chemical entities, or have a novel use, such as those described by the International Pharmaceutical Excipients Council (IPEC) Europe’s position paper Excipient Master File Systems in Europe. These are classed as novel excipients.

‘We have to follow a risk-based approach,’ says Heubner. ’So novel excipients have to be treated differently from common excipients, but the system should not be too complicated. We should keep it simple.’ Classification sits alongside a general manufacturing and general distribution standards regime aimed at improving assurance of excipient quality and safety and facilitating trade.

‘We need to classify excipients, but we also need standardisation on how excipients are to be manufactured – is it GMP, is it based on International Conference on Harmonization (ICH) guidelines, is it based on International Organization for Standardisation (ISO) guidelines, and so on,’ says Heubner. ‘Then we need to educate auditors, so you have audits and still have the auditors inspected by the regulatory authorities.’

Towards a solutionWhile an agreed certification solution is unlikely to be reached overnight, there is already considerable progress being made. There was broad agreement at a stakeholder meeting held in Brussels in May 2009 on the way forward regarding the need to define the standards and to classify excipients. Encouragingly there is also participation of a number of affected industry groupines, the EFCG, IPEC US, IPEC Europe, the European Association of Chemical Distributors (FECC) and the Pharmaceutical Quality

Group (PQG), with dedicated working groups on classification, certification and auditing,

coordinated by a global steering team.

The global aspect is very important; operating in a global world, global

solutions are required. ‘What we need, and what we are working for, is a global

system, not something that has to be adapted to various individual regions of the world,’ says Heubner.

From the perspective of the certification working group a

framework for a certification system for excipients could be agreed on by as early as the second quarter of 2010, says Heubner. However, there will also need to be a lengthy process of negotiations with the various competent authorities around the world, such as the US FDA and the European Commission. The whole process will, says Heubner, take several years.

In the meantime, however, if there are generally agreed guidelines and customers want to use them, then there will be a ’soft launch’ of the classification and standards, which will be good news for patients and consumers. In most industries when there is an obvious need for quality assurance, standardisation, classification and other forms of governance and regulation, corporations operating in that industry press strongly for self-regulation over national and supra-national governmental action. The call for regulation is more often driven by consumers and legislators.

In the case of controlling excipient quality, however, it is a broad swathe of excipient producers pushing for international regulation. To the majority of producers and stakeholders, to Heubner and to the EFCG, it makes perfect sense. ‘It is true that when we had our first meetings with the authorities, and told them that we wanted more regulation, they said that it was the first time an industry had come to them and asked for greater regulation of their activities,’ says Heubner. ‘But we are all patients, we are all consumers – we do this for our own safety.’ WPF

THE EXCIPIENT MARKET

Although excipients make up the major proportion of the content of medicines, they constitute a much smaller proportion in terms of value.

‘Excipients account for a global turnover of less than €4–5 billion, so it is an absolutely tiny proportion of the final drug value, so the regulation of excipients will not increase the price of the final medicine,’ says Heubner.

‘Out of the €4–5 billion, I would say that about 80%is produced in Europe and the US, and 20–30% originates from the Far East including India and China.’

THE COUNTERFEITING CONUNDRUM

If there is one activity that threatens to undermine the good work done by industry groups, legislators and international regulatory bodies, to ensure the safety of APIs and excipients in pharmaceuticals it is piracy and counterfeiting.

The World Health Organisation has estimated that around 50% of all global pharmaceuticals may be counterfeit. And the counterfeiters have no regard for certification systems or production quality standards.

‘I think it is a big problem,’ says Heubner. ‘At our recent EFCG conference, one speaker estimated that more than 20% of the older, well-established medicines Europe, are falsified at API level. As long as you can make a business out of using substandard ingredients, and there are no deterrents against doing so, then you will have fraud, falsification and counterfeiting. It is an issue that has to be addressed at a national authority level by national governments because existing European law requires them to deal with the issue.’

to be treated differently from common

Group (PQG), with dedicated working groups on classification, certification and auditing,

coordinated by a global steering team.

The global aspect is very important; operating in a global world, global

solutions are required. ‘What we need, and what we are working for, is a global

system, not something that has to be

to be addressed at a national authority level by national governments because existing European law requires them to deal with the issue.’

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