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Regulators hope new standards will stop illegal drug imports, but manufacturers fear they may stifle innovation.
The European Union is introducing a system for implementing standards of good manufacturing practices for medicine excipients after a long campaign for the imposition of GMP standards by excipient manufacturers in the region. The move follows the creation of new EU rules for GMP standards for imported APIs; full enforcement began this summer.
The imposition of the two sets of GMP standards, which is laid down in the EU’s Falsified Medicines Directive (FMD), is seen by European manufacturers of active substances and excipients as necessary to stop the increasing numbers of substandard products imported into the EU in recent years, particularly from Asia.
In addition to the GMP initiative with excipients, the EU has also been tightening up rules on other quality issues, such as the use of certain phthalate ingredients because of their possible adverse effect on human reproduction and development. The London-based European Medicines Agency (EMA), responsible for centralized pharmaceutical regulation in the EU, has been drawing up stricter rules on information of excipients in labels and product leaflets.
Excipient manufacturers in Europe, while welcoming the tougher quality standards, reckon that the EU and national regulatory authorities are still not doing enough to encourage innovation, according to the International Pharmaceutical Excipients Council (IPEC). In particular, they are continuing to press for the introduction of an excipients master file system, the absence of which is putting the EU regulators out of line with those in the US, Canada, Australia, and other developed countries.
“There is a lot of regulatory activity in the EU at the moment with excipients with the objective of giving European producers more of a level playing field internationally,” explains Kate Denton, a regulatory affairs manager at Novozymes Biopharma UK Ltd., Nottingham, UK, a maker of biopharmaceutical excipients and part of the Danish-based Novozymes group. “Now is a good opportunity to do something about the lack of an excipients master file, which has become a barrier to innovation in Europe,” she tells BioPharm International.
On GMP for excipients, the European Commission has been finalizing details of a guideline after issuing a draft with a consultation period that ended in April of this year. The finalized version looks likely to be similar to the Quality Management System of the International Organisation for Standardisation (ISO 9001:2008) and to a joint guideline of IPEC and the London-based Pharmaceutical Quality Group (PQG).
Under the FMD approved two years ago, marketing authorization holders have to ensure that “the excipients are suitable for use in medicinal products by ascertaining what the appropriate good manufacturing practice is” (1). In the EU’s draft guideline, the quality risk management principles of the International Conference on Harmonisation (ICH) would be used to categorize the excipients as being of “low,” “medium,” or “high” risk to determine the appropriate GMP. This risk assessment would take into account the potential for microbiological or viral contamination and for impurities originating from raw materials.
Mechanisms are now being put in place for third-party auditing schemes generating single certificates covering both GMP and good distribution practice (GDP), which are acceptable to pharmaceutical manufacturers and the regulatory authorities in Europe.
The main organizations carrying out the audits in Europe are likely to be the US-based Rx-360 International Pharmaceutical Supply Chain Consortium and EXCiPACT, Brussels. EXCiPACT has been set up by four groups--IPEC, PQG, European Fine Chemicals Group (EFCG), and the Federation of European Chemical Distributors (FECC). So far the organization has certified two auditing organizations to carry out its audits with two excipient producers in Germany already receiving certificates and three others for European manufacturers close to being issued. The GMP standard being used by EXCiPACT is based on the ISO 2001 and IPEC-PQG guideline and will be broadly similar to the one being finalized by the European Commission.
“We have got a momentum going,” says Tony Scott, a UK consultant working for EXCiPACT. “An acceptable third-party auditing system for issuing single certificates is essential if the EU’s requirement for GMP compliance is going to work. Otherwise excipient producers and suppliers will be overwhelmed with visits by auditors.” The third-party auditing system will cover mainly low- and medium-risk excipients and some high-risk ones. “We’ll be dealing with the 90% of excipients considered to be safe,” Scott told BioPharm International.
In a virtual category of their own are novel excipients whose ingredients, modes of action, or other aspects of their performance manufacturers want to keep confidential. Also regulators have to cope with an absence of other products with which to compare them in order to assess their safety.
The major impetus behind innovation in excipients is the need to help with problems like poor solubility, absorption, and stability of active substances. “The development of new molecular structures in excipients can be a big challenge for excipient producers because they have to finance their own toxicity and tolerance studies, which can be very expensive,” explains Professor Rainer Mueller, founder of Pharmasol, Berlin, a producer of solid lipid nanoparticle (SLN) excipients. “With classes of new chemical entities, excipient manufacturers are avoiding being the first ones on the market so that they have the responsibility to carry out the first safety studies,” he continued. “If you’re not the first, the costs would be lower.”
Although marketed as nanoparticles, Pharmasol’s lipid particles fall outside the official EU definition of “nano” because they are larger than 100 nm. “If they were smaller we would also be required to carry out toxicity and other studies,” he said.
Nonetheless, in a recent reflection paper, the EMA indicated that with nanoparticles falling within the EU definition and with other innovative excipient materials, there were possible advantages in not being the first on the market (2). This would particularly be the case if the product could be demonstrated to be similar to or a follow-on of a previously marketed product, the paper says.
“Formulation scientists prefer excipients that have a pre-approved functional role in drug products and a pharmacopeia monograph in order to avoid additional risks in the approval process,” says Francois Scheffler, head of global marketing pharma ingredients at BASF. “In this situation, it is typical for the transition from novel excipient to commonly accepted excipient to take from 7-10 years,” he adds.
The European branch of IPEC believes that the commercialization timeframe for novel excipients would be much shorter if the EU accepted a system for excipient master files (3). The files would consist of a closed part with confidential information accessible only to the regulator and an open part for the pharmaceutical manufacturer to enable it to ensure the efficiency, efficacy, and quality of the medicine.
A direct approval process based on a master file system would “simplify the overall drug approval process and as a consequence accelerate drug development and, therefore, drug launches,” says Scheffler. “That would foster innovation and ultimately improve treatment options for patients,” he adds.
The EMA has set up a working group to investigate possible improvements to the EU master file system for active ingredients. IPEC and other groups argue that the system of master files for actives could be extended to cover excipients (3).
The regulatory authorities acknowledge the arguments in favor of an excipient master file procedure but argue that the introduction of one is not a priority since improvements to other parts of the approval process are more urgent. Excipient producers, however, point out that novel excipients hold the key to making a wider range of drug more beneficial to patients by enhancing their delivery capabilities. “The European authorities are out of sync with the rest of the world with efforts to encourage innovation through harmonization of procedures,” says Denton.
1. EC, Directive 2011/83/EC, article 46(f).
2. EMA, Reflection Paper on Surface Coatings: General Issues for Consideration Regarding Parenteral Administration of Coated Nanomedicine Products, EMA/325027/2013.
3. IPEC Europe, IPEC Europe Approach to the Lack of a Master File System for Excipients in Europe, Dec. 21, 2009, www.ipec-europe.org/UPLOADS/
About the Author
Sean Milmo is a freelance writer based in Essex, UK, email@example.com.