Regulation of Pharma Excipients in Europe: Implications for Manufacturers and Suppliers

Pharmaceutical manufacturers and their excipient suppliers are facing an uncertain future with the formal introduction of Good Manufacturing Practice (GMP) requirements in the European Union. However, there is still considerable debate about the form these will take as well as opportunities for stakeholders to have their say.

The European Commission says it has a clear mandate to draw up legislation, at least for some high-risk excipients (see Table 1), in the interest of public health. This stems from a series of cases in which excipients have caused in major public health problems as well as from other concerns including the possibility of transmissible spongiform encephalopathy (TSE) contamination in animal derived excipients.
In 2006, 21 people died in Panama after taking a government-made cough syrup containing diethylene glycol that had been mislabeled as glycerol, a widely used excipient. Another 38 people suffered side effects including disorientation and kidney failure.

Several countries, including Panama, issued a major recall of toothpaste made in China in 2007 because it contained diethylene glycol that had again been mislabeled as glycerol. While no deaths were reported in this case, previous contamination episodes involving medicines have been far more serious. In 1996, glycerol contaminated with diethylene glycol killed 88 people in Haiti, while in 1990-1992 paracetamol syrup contaminated with diethylene glycol from propylene glycol led to 236 deaths in India and Bangladesh. In 1990, 47 people died in Nigeria after taking cough syrup contaminated with solvents.

The complex supply chain in the Panama case, which saw the glycerol/diethylene glycol pass from a supplier in China not registered to supply pharmaceutical-grade products through the hands of several companies and traders before being bought by the Panamanian government. This illustrates the view that, in most cases, problems with excipients have occurred because of a failure in good distribution practice (GDP) rather than GMP.

The Commission's aim is to develop a set of agreed guidelines, incorporating both GMP and GDP, which will harmonize the regulation of excipients. The EC has already completed a major overhaul of pharmaceutical legislation and brought in new GMP standards for active pharmaceutical ingredients (APIs) as part of Directive 2004/27/EC.

Critically, this reform has made the extension of GMP requirements to at least some excipients inevitable, as Directive 2004/27/EC states that "this point (GMP for starting materials) shall also be applicable to certain excipients, the list of which as well as the specific conditions of application shall be established by a Directive adopted by the Commission."

The scope of such a Directive is clear and designed to safeguard supply chains in Europe regardless of the source of ingredients. It will apply to both total and partial manufacture or import of starting materials, and the various processes of dividing up, packaging or presentation of the starting materials prior to its incorporation into a medicinal product. This includes repackaging or re-labeling, such as might be carried out by a distributor.

A draft Directive entitled "Specific Conditions on the Application of Principles and Guidelines of GMP for Certain Excipients" was drawn up in December 2006. The main topics covered by the Draft can be seen in Table 2.
Public health problems in recent years put the need for some form of GMP for excipients beyond doubt. The debate at the moment is all about setting GMP requirements appropriate to excipients, and not simply mirroring those developed for active pharmaceutical ingredients.

Excipient industry
A key barrier to developing effective legislation has been the disparate nature of the excipient market, with players in the sector spanning commodity food ingredient manufacturers through to companies that specialize in functional ingredients for pharmaceuticals. Overall, more than 1,200 excipients are used in medicinal products - not including colors and flavors - but only about 300-400 have monographs in recognized pharmacopoeia.

This wide range of excipients - from simple sugars to complex polymers - means that 'pharmaceutical' GMP standards, i.e. those enshrined in Eudralex vol IV Part 2 for active pharmaceutical ingredients, are unlikely to be appropriate for all but a handful of excipients. Meanwhile, other standards such as ISO 9001, widely used in other industries such as food, do not go far enough.

For example, Part 2 calls for full 'three batch' validation programs as is standard in the pharmaceutical world, but it is unlikely that a manufacturer of a simple 'food ingredient' with minimal pharmaceutical use would do this. In reality, for such excipients it should be sufficient to demonstrate consistency, for example using capability studies.

Likewise, Part 2 also demands full ongoing stability studies for active pharmaceutical ingredients, while for excipients it should be possible to refer to historical data, given that the shelf life of many common excipients is well defined.

So for manufacturers of ingredients and medicines alike, there is uncertainty about the GMP standards, which may be required in the forthcoming EC Directive, and questions remain about how those standards will be monitored and enforced in practice.

Added to that is the fear that if the regulations are too strict or require major administrative, operational and/or capital expenditures, some suppliers may choose to exit the market for pharmaceutical excipients altogether. This is particularly likely for companies whose sales to the pharmaceutical industry may represent only a small part of their overall business.

The consequences
The consequences for pharmaceutical companies could be damaging and expensive. One option is of course to find a new supplier, although this could require additional stability and/or bioequivalence studies to assure the clinical performance of the affected product is not compromised. If another supplier proves hard to locate, they may be forced to reformulate with a new excipient, which could involve new clinical studies. In extreme cases pharmaceutical companies may decide the only option is to withdraw a product, and this in turn could have health care and legal consequences.

Adoption of GMP for excipients is also likely to have a major impact on pharmaceutical manufacturers in terms of the quality assurance process. They have the responsibility to ensure that listed excipients are compliant, and should ideally inspect their suppliers' manufacturing sites and processes. This could mean that companies have to inspect an increasingly large number of suppliers, and indeed that suppliers themselves face multiple inspections that could prove impossible to cope with.

Assurance problems could also arise if pharmaceutical companies are denied access to an audit, or indeed if the supply chain is complex and involves suppliers outside the EU. Pharmaceutical products manufactured outside the EU or under contract also raise assurance issues as pharmaceutical companies cannot readily test for compliance, yet the Qualified Person (QP) signing off for sale must ensure that any listed excipients contained in them were manufactured in accordance with EU excipient GMP. A system will therefore need to be developed so to ensure that only excipients made to EU GMP guidelines have been used - perhaps by writing this into contracts. Consideration also has to be given to how manufacturing changes made by suppliers could affect compliance with EU excipient GMP.

Commission consultation
Mindful of the possible consequences of the proposed legislation, the Commission has initiated consultations to gauge the impact of the legislation in its draft form, identify what quality systems are already being used by companies and identify areas where modifications need to be made.

It has developed two questionnaires: one for excipient manufactures (which can also be completed by distributors) and another for excipient users and distributors. They had a deadline of July 30, 2007 for submission, but feedback from this process is still awaited.

The consultation process at the EC could lead to several possible outcomes. One is that it results in the formation of formal legislation, including GMP principles as outlined in draft guidelines issued in December.

The Commission could also opt for a more hands-off approach, for example by adopting detailed guidelines similar to those in the GMP Guide for Pharmaceutical Excipients drawn up by the International Pharmaceutical Excipients Council (IPEC) and Pharmaceutical Quality Group (PQG)in 2006 that aims to provide harmonized guidance for excipients and takes into account the existing standards that manufacturers have been using.

Alternatively, it could opt for risk-management principles and tools, such as those laid out in the International Conference on Harmonization (ICH Q9) framework, and allow the industry to self-regulate by applying its own GMP principles based on an assessment of risks to the patient.

The hope is that for some manufacturers the EC's deliberations could simply be a formalization of the quality standards they are already applying in practice, as some companies have already adopted GMP systems in accordance with the IPEC/PQG guide.

Developments outside the EU
The current concerns about health risks posed by fraudulent, contaminated or poor excipients are being mirrored by regulators elsewhere, notably the USA and China. In the US, for example, the Food and Drug Administration (FDA) recently published non-binding guidance that asks for testing of every received container of glycerin for diethyl glycol as part of an effort to draw attention to the possible risks to public health from contaminated or mislabeled excipients.

Meanwhile, China has tabled its own legislation on GMP for excipients and - perhaps stung by the negative publicity about the products tainted from use of Chinese ingredients and allegations of weak enforcement of regulations - announced in June 2007 it plans to go even further, implementing a series of new controls on food and drug imports and exports as well as random testing of medicines for quality.

In Europe it is encouraging that the Commission has embarked on such an inclusive consultation procedure, and the hope is that it will be successful in formulating legislation which strikes the right balance between avoiding risks to public health from quality-impaired products, and avoiding excessive regulation that could affect the ability of suppliers to supply the market.

At the moment, the identity of the actual list of excipients that look set to come under the EC's regulatory oversight is currently under discussion, but a short-list of candidate groups has been established based on the probability and severity of adverse events that could occur (see Table 1).

Excipients on the list are those known to have history of problems, such as glycerol, or those which have a high-risk route of administration, have an important function in the medicinal product, are used in high quantities or in products that patients take over a long period, or are biologically derived. Other considerations include, for example, whether the excipient is made in multipurpose or multiprocess plant, which could increase the risk of contamination.

Table 1
Table 2